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Background: The role of HOXA9 requires investigations in pancreatic ductal adenocarcinoma (PDAC) as HOXA9 inhibitors are being developed. HOXA9 might attract CD163 expressed tumor associated macrophages (TAM) and could affect PDAC prognosis. This work aims to study the expression and relevance of HOXA9 and CD163 in PDAC progression. Materials and methods: Selected 98 PDAC and 98 adjacent non tumor tissues as a control group were immunostained with HOXA9 and CD163 antibodies. Results: PDAC displayed highly significant higher HOXA9 staining intensity, percent and H score values than control group. HOXA9 staining of PDAC cases showed significant associations with poor prognostic indicators including larger tumor size, higher grade and advanced stage. PDAC showed highly significant differences regarding CD163 macrophage-specific staining intensity, percent and H score values than control group. CD163 showed significant higher expressions with larger tumor size, higher histological grade and advanced stage group. HOXA9 staining in PDAC showed highly significant direct correlations with CD163 positive macrophages. Follow up of PDAC cases revealed that high median H score of HOXA9 and CD163 were significantly associated with worse overall survival. CD163 was an independent prognostic marker of worse survival. Conclusions: In conclusion, HOXA9 could potentiate PDAC progression by stimulating CD163 expressed TAM attraction in tumors. HOXA9 and CD163 could participate in PDAC therapy. HOXA9 and CD163 could be predictors of worse prognosis and shorter survival in PDAC. [ABSTRACT FROM AUTHOR]

Soluble CD163 (sCD163) is a circulating inflammatory mediator, indicative of acute and chronic, systemic and non-systemic inflammatory conditions. It is the cleavage outcome, consisting of almost the entire extracellular domain, of the CD163, a receptor expressed in monocytic lineages. Its expression is proportional to the abundance of CD163+ macrophages. Various mechanisms trigger the shedding of the CD163 receptor or the accumulation of CD163-expressing macrophages, inducing the sCD163 concentration in the circulation and bodily fluids. The activities of sCD163 range from hemoglobin (Hb) scavenging, macrophage marker, decoy receptor for cytokines, participation in immune defense mechanisms, and paracrine effects in various tissues, including the endothelium. It is an established marker of macrophage activation and thus participates in many diseases, including chronic inflammatory conditions, such as atherosclerosis, asthma, and rheumatoid arthritis; acute inflammatory conditions, such as sepsis, hepatitis, and malaria; insulin resistance; diabetes; and tumors. The sCD163 levels have been correlated with the severity, stage of the disease, and clinical outcome for many of these conditions. This review article summarizes the expression and role of sCD163 and its precursor protein, CD163, outlines the sCD163 generation mechanisms, the biological activities, and the known underlying molecular mechanisms, with an emphasis on its impact on the endothelium and its contribution in the pathophysiology of human diseases. [ABSTRACT FROM AUTHOR]

Background: Distal bile duct cancer is an aggressive malignancy. Tumor-infiltrating immune cells (TIICs) in the tumor microenvironment are crucial for predicting prognosis in various cancers. In this study, we analyzed TIICs based on CD11b, CD163, and CD8 expression, and evaluated their association with clinicopathologic factors and prognosis in distal bile duct cancer. Methods: A total of 90 patients who underwent curative resection for distal bile duct cancer were enrolled. We analyzed CD11b+ tumor-infiltrating myeloid cells (TIMs), CD163+ tumor-infiltrating macrophages (TAMs), and CD8+ tumor-infiltrating lymphocytes (TILs) using immunohistochemistry and tissue microarrays. The correlation between TIICs and clinicopathologic characteristics was assessed. Results: Low levels of CD11b+ TIMs (p < 0.001) and high levels of CD8+ TILs (p = 0.003) were significantly associated with improved overall survival (OS). A combined low level of CD11b+ TIMs and high level of CD8+ TILs was identified as an independent favorable prognostic factor (hazard ratio, 0.159; confidence interval, 0.061–0.410; p < 0.001). Conclusions: CD11b+ TIMs play a crucial role in the tumor microenvironment and the prognosis of distal bile duct cancer. The combined analysis of CD11b+ TIMs and CD8+ TILs can predict survival in patients with distal bile duct cancer. [ABSTRACT FROM AUTHOR]

African Swine Fever Virus (ASFV), resulting in strain-dependent vascular pathology, leading to hemorrhagic fever, is an important pathogen in swine. The pathogenesis of ASFV is determined by the array and spatial distribution of susceptible cells within the host. In this study, the replication characteristics of ASFV genotype I E70 (G1-E70) and ASFV genotype II Belgium 2018/1 (G2-B18) in the environment of small veins were investigated in an established vein explant model. Immunofluorescence staining analysis revealed that perivenous macrophages (CD163+ cells) were widely distributed in the explant, with most of them (approximately 2–10 cells/0.03 mm2) being present close to the vein (within a radius of 0–348 µm). Upon inoculation with G1-E70 and G2-B18, we observed an increase in the quantity of cells testing positive for viral antigens over time. G1-E70 replicated more efficiently than G2-B18 in the vein explants (7.6-fold for the ear explant at 72 hpi). The majority of ASFV+ cells were CD163+, indicating that macrophages are the primary target cells. Additional identification of cells infected with ASFV revealed the presence of vimentin+, CD14+, and VWF+ cells, demonstrating the cellular diversity and complexity associated with ASFV infection. By the use of this new vein explant model, the susceptibility of vascular and perivascular cells to an ASFV infection was identified. With this model, it will be possible now to conduct more functional analyses to get better insights into the pathogenesis of ASFV-induced hemorrhages. [ABSTRACT FROM AUTHOR]

Background: Oral lichen planus is a well-known chronic inflammatory mucocutaneous disorder, which has clinical and histological presentation that mimics oral lichenoid reaction. According to the fifth edition of WHO, both conditions are considered as oral potentially malignant disorders. Recent studies on oral potential disorders documented deregulation of some signaling molecules related to the Wnt/β-catenin pathway. Therefore this study aimed to compare the immune expression of β-catenin & CD163 in dysplastic /non-dysplastic cases of Oral lichen planus & oral lichenoid lesion. In addition, a statistical correlation between both immune markers was done regardless of the type of the study group. Methods: Four study groups were designated as 2 groups of Oral lichen planus (one dysplastic & one non –dysplastic) and the other 2 groups were oral lichenoid lesions (one dysplastic & one non –dysplastic). Ten cases in each group were collected and investigated by immunohistochemistry. The area percent of beta catenin and also counting of m2 macrophages expressing + CD163 marker was calculated in the study groups. Results: The Statistical analysis highlighted a statistically significant difference between the studied groups. Moreover, Pearson correlation test reported a significant moderate positive correlation between beta catenin & CD163 expression in the studied cases. Conclusion: Our findings supported new perceptions of the mechanism by which tumor associated macrophage specific β-catenin signaling promotes the aggressive behavior of oral potential malignant disorders. Clinical relevance: Evidence of the relationship between beta catenin and M2 macrophages (+ CD163) may enhance the development of macrophage-based strategies for treatment and improve the prognosis of such cases. [ABSTRACT FROM AUTHOR]

Background: Tongue defects have several etiologies and significantly affect the quality of life. This study was conducted to compare the regenerative potential of erythropoietin (EPO)-loaded hydrogel and adipose derived stem cell (ADSC) secretome on tongue dorsum defects focusing on the role of anti-inflammatory M2 macrophage phenotype. Methods: Rats were subjected to induction of mechanical circular defects on the dorsal surface of the tongue, then divided into three groups; Group I (control): received 0.1 ml phosphate buffered saline, Group II (EPO): received 5000 U/kg EPO-hydrogel, and Group III (ADSC-Secretome): received 0.1 ml ADSC-Secretome. Treatments were injected circumferentially around wound margins after induction. Seven and fourteen days after treatment, specimens were obtained and processed for histological and immunohistochemical staining followed by the relevant histomorphometric and statistical analyses. Results: Seven days after treatment, groups II and III presented defects with some epithelial regeneration at the lateral margins, while the center of the defect showed granulation tissue with much inflammatory cells. The base of the defects showed some muscle fibers and new blood vessels, however group III showed more enhanced neovascularization. Fourteen days after therapeutic intervention, group II defects were completely covered with epithelium showing a thin keratin layer with regular rete pegs interdigitating with the underlying connective tissue papillae, but tongue papillae were not restored. Group III expressed much better healing with developing filiform papillae. The connective tissue showed more vascularity and well-arranged muscle bundles. Both treated groups showed a significant decrease in defect depth and significant increase in anti-inflammatory macrophages compared to the control group at both time intervals, however there was no significant difference between the two treated groups. Conclusion: Both treatments showed promising and comparable results in the treatment of tongue defects reducing inflammation and restoring tongue histological architecture with significant upregulation of M2 macrophage. [ABSTRACT FROM AUTHOR]

CD163, a scavenger receptor with anti-inflammatory function expressed exclusively on monocytes/macrophages, is dysregulated in cases of diabetes complications. This study aimed to characterize circulating CD163+ monocytes in the presence (D+Comps) or absence (D−Comps) of diabetes-related complications. RNA-sequencing and mass cytometry were conducted on CD163+ monocytes in adults with long-duration diabetes and D+Comps or D−Comps. Out of 10,868 differentially expressed genes identified between D+Comps and D−Comps, 885 were up-regulated and 190 were down-regulated with a ≥ 1.5-fold change. In D+Comps, 'regulation of centrosome cycle' genes were enriched 6.7-fold compared to the reference genome. MIR27A, MIR3648-1, and MIR23A, the most up-regulated and CD200R1, the most down-regulated gene, were detected in D+Comps from the list of 75 'genes of interest'. CD163+ monocytes in D+Comps had a low proportion of recruitment markers CCR5, CD11b, CD11c, CD31, and immune regulation markers CD39 and CD86. A gene–protein network identified down-regulated TLR4 and CD11b as 'hub-nodes'. In conclusion, this study reports novel insights into CD163+ monocyte dysregulation in diabetes-related complications. Enriched centrosome cycle genes and up-regulated miRNAs linked to apoptosis, coupled with down-regulated monocyte activation, recruitment, and immune regulation, suggest functionally distinct CD163+ monocytes in cases of diabetes complications. Further investigation is needed to confirm their role in diabetes-related tissue damage. [ABSTRACT FROM AUTHOR]

Objective: Osteoclast (OC) over-activation is an important cause of bone loss that is strongly correlated with inflammation. Although the CD163/TWEAK/Fn14 axis has been implicated in several inflammatory pathologies, its contributions to inflammatory bone loss remain poorly understood. This study aimed to evaluate the interaction of the CD163/TWEAK/Fn14 axis with OC in inflammatory bone loss. Methods: To assess the role of CD163 in bone homeostasis, we characterized the bone phenotypes of CD163-deficient mice and their wild-type littermates. CD163 and TWEAK levels were evaluated in the bone marrow of mice with LPS-induced bone loss and individuals with rheumatoid arthritis (RA). Bone mass changes were assessed using uCT and histology following supplementation with recombinant mouse CD163 protein (rCD163) or blockade of TWEAK/Fn14 signaling in CD163-deficient mice and mice with LPS-induced bone loss. The impact of CD163/TWEAK on OC differentiation and bone resorption capacity was analyzed in vitro. Results: CD163 deficiency caused decreased bone mass and increased OC abundance. Lower CD163 expression and higher TWEAK expression were observed in the bone marrow of mice with LPS-induced bone loss and individuals with RA. TWEAK, mainly derived from CD68+ macrophages, was responsible for bone loss, and supplementing rCD163 or blocking TWEAK/Fn14 signaling contributed to rescue bone loss. TWEAK/Fn14 synergistically promoted RANKL-dependent OC differentiation and bone resorption capability through downstream mitogen-activated protein kinases (MAPK) signaling, while the pro-osteoclastic effect of TWEAK was suppressed by CD163. Conclusion: Our findings suggest that the CD163/TWEAK/Fn14 axis is a potential therapeutic target for inflammatory bone loss by regulating osteoclastogenesis.

Abstract Background The role of HOXA9 requires investigations in pancreatic ductal adenocarcinoma (PDAC) as HOXA9 inhibitors are being developed. HOXA9 might attract CD163 expressed tumor associated macrophages (TAM) and could affect PDAC prognosis. This work aims to study the expression and relevance of HOXA9 and CD163 in PDAC progression. Materials and methods Selected 98 PDAC and 98 adjacent non tumor tissues as a control group were immunostained with HOXA9 and CD163 antibodies. Results PDAC displayed highly significant higher HOXA9 staining intensity, percent and H score values than control group. HOXA9 staining of PDAC cases showed significant associations with poor prognostic indicators including larger tumor size, higher grade and advanced stage. PDAC showed highly significant differences regarding CD163 macrophage-specific staining intensity, percent and H score values than control group. CD163 showed significant higher expressions with larger tumor size, higher histological grade and advanced stage group. HOXA9 staining in PDAC showed highly significant direct correlations with CD163 positive macrophages. Follow up of PDAC cases revealed that high median H score of HOXA9 and CD163 were significantly associated with worse overall survival. CD163 was an independent prognostic marker of worse survival. Conclusions In conclusion, HOXA9 could potentiate PDAC progression by stimulating CD163 expressed TAM attraction in tumors. HOXA9 and CD163 could participate in PDAC therapy. HOXA9 and CD163 could be predictors of worse prognosis and shorter survival in PDAC.

Abstract Background Oral lichen planus is a well-known chronic inflammatory mucocutaneous disorder, which has clinical and histological presentation that mimics oral lichenoid reaction. According to the fifth edition of WHO, both conditions are considered as oral potentially malignant disorders. Recent studies on oral potential disorders documented deregulation of some signaling molecules related to the Wnt/β-catenin pathway. Therefore this study aimed to compare the immune expression of β-catenin & CD163 in dysplastic /non-dysplastic cases of Oral lichen planus & oral lichenoid lesion. In addition, a statistical correlation between both immune markers was done regardless of the type of the study group. Methods Four study groups were designated as 2 groups of Oral lichen planus (one dysplastic & one non –dysplastic) and the other 2 groups were oral lichenoid lesions (one dysplastic & one non –dysplastic). Ten cases in each group were collected and investigated by immunohistochemistry. The area percent of beta catenin and also counting of m2 macrophages expressing + CD163 marker was calculated in the study groups. Results The Statistical analysis highlighted a statistically significant difference between the studied groups. Moreover, Pearson correlation test reported a significant moderate positive correlation between beta catenin & CD163 expression in the studied cases. Conclusion Our findings supported new perceptions of the mechanism by which tumor associated macrophage specific β-catenin signaling promotes the aggressive behavior of oral potential malignant disorders. Clinical relevance Evidence of the relationship between beta catenin and M2 macrophages (+ CD163) may enhance the development of macrophage-based strategies for treatment and improve the prognosis of such cases.

Sickle cell disease (SCD)-associated chronic hemolysis promotes oxidative stress, inflammation, and thrombosis leading to organ damage, including liver damage. Hemoglobin scavenger receptor CD163 plays a protective role in SCD by scavenging both hemoglobin-haptoglobin complexes and cell-free hemoglobin. A limited number of studies in the past have shown a positive correlation of CD163 expression with poor disease outcomes in patients with SCD. However, the role and regulation of CD163 in SCD-related hepatobiliary injury have not been fully elucidated yet. Here we show that chronic liver injury in SCD patients is associated with elevated levels of hepatic membrane-bound CD163. Hemolysis and increase in hepatic heme, hemoglobin, and iron levels elevate CD163 expression in the SCD mouse liver. Mechanistically we show that heme oxygenase-1 (HO-1) positively regulates membrane-bound CD163 expression independent of nuclear factor erythroid 2-related factor 2 (NRF2) signaling in SCD liver. We further demonstrate that the interaction between CD163 and HO-1 is not dependent on CD163-hemoglobin binding. These findings indicate that CD163 is a potential biomarker of SCD-associated hepatobiliary injury. Understanding the role of HO-1 in membrane-bound CD163 regulation may help identify novel therapeutic targets for hemolysis-induced chronic liver injury. [ABSTRACT FROM AUTHOR]

Background and Objectives: This study presents a retrospective analysis of 26 autopsy cases from a single centre, primarily focusing on forensic cases, with a majority of male individuals. Materials and Methods: We systematically analysed autopsy reports and cardiac tissue slides using haematoxylin-eosin stain and immunohistochemistry for CD3, CD163, and IL-6. The histological assessment evaluated key variables such as inflammation severity, necrosis, and background changes using a standardised grading system. Quantitative analysis of immunohistochemical markers was performed, calculating the percentage of positively stained cells within the inflammatory infiltrate. Results: The average age was 51.6 years, slightly skewed towards older males. The fatalities varied widely, with sudden death and drug abuse being the most common conditions linked to myocarditis findings on histological examination. A strong correlation was found between the severity of inflammation (measured by size within a myocardium section) and the scoring system based on the number of inflammatory foci per section (p ≤ 0.001). Most cases showed mild to minimal fibrosis, with some exhibiting moderate to severe fibrosis, arteriosclerosis, and myocyte hypertrophy. The presence of protein CD3 in the inflammatory infiltrate revealed a moderate inverse correlation between the CD3 values and the severity of inflammation and necrosis, and a strong inverse correlation with neutrophil levels. CD3 levels were higher in sudden death cases and lower in cases with numerous inflammatory foci, highlighting the discreet nature of lymphocytic myocarditis. Macrophage presence, assessed using CD163, showed a moderate inverse correlation with neutrophil levels and significant differences between sudden death and non-sudden death cases. Macrophage-rich inflammation was observed in cases with pneumonia/bronchopneumonia-associated lesions. IL-6 expression showed a moderate direct correlation with inflammation severity (p = 0.028), severity of necrosis (p = 0.005), and the number of inflammatory foci per section (p = 0.047). A moderate inverse correlation was found between CD3 and IL-6 expression (p = 0.005). Conclusions: These findings highlight the need for a unique immunohistochemical approach in forensic cases of myocarditis, differing from guidelines for endomyocardial biopsies due to diverse inflammatory cells. The study suggests exploring inflammatory chemokines within myocarditis foci for their significance in clinical scenarios. Specifically, IL-6, a crucial pro-inflammatory interleukin, correlated significantly with the severity of inflammation and necrosis (p < 0.05). This study provides novel and valuable insights into the histopathological and immunological markers of myocarditis in autopsy cases. [ABSTRACT FROM AUTHOR]

Background: Immunological imbalances characteristic of endometriosis may develop as early as the primary manifestations of the disease in adolescence. Objective: To evaluate subpopulation dynamics of monocytes and lymphocytes in peripheral blood and peritoneal fluid of adolescents with peritoneal endometriosis at diagnosis and after 1-year progestogen therapy. Methods: This study included 70 girls, 13–17 years old, diagnosed laparoscopically with peritoneal endometriosis (n = 50, main group) or paramesonephric cysts (n = 20, comparison group). Phenotypes of monocytes and lymphocytes of the blood and macrophages of the peritoneal fluid were analyzed by flow cytometry at diagnosis and during progestogen therapy. Results: Differential blood counts of CD16+ (p < 0.001) and CD86+ (p = 0.017) monocytes were identified as independent risk factors for peritoneal endometriosis in adolescents. During the treatment, cytotoxic lymphocytes CD56dimCD16bright (p = 0.049) and CD206+ monocytes (p < 0.001) significantly increased while CD163+ monocytes decreased in number (p = 0.017). The CD56dimCD16bright blood counts before (p < 0.001) and during progestogen therapy (p = 0.006), as well as CD206+ blood counts during the treatment (p = 0.038), were associated with the efficacy of pain relief after 1-year progestogen therapy. Conclusions: Adolescents with peritoneal endometriosis have altered counts of pro- and anti-inflammatory monocytes and lymphocytes both before and after 1-year progestogen therapy, correlating with treatment efficacy and justifying long-term hormonal therapy. [ABSTRACT FROM AUTHOR]

Background: Early and late-onset neonatal sepsis (EOS and LOS) are significant causes of morbidity and mortality in newborns. Accurate and timely diagnosis is critical for effective management. The Cluster of Differentiation 163 (CD163) level in the blood has emerged as a potential biomarker for sepsis, reflecting the immune response to infection. Objective: This study aimed to evaluate the role of CD163 levels in predicting neonatal sepsis and its correlation with other clinical and laboratory parameters. Methods: A comparative study was conducted involving 90 neonates divided into three groups: EOS, LOS, and a control group. Clinical data, presenting complaints, maternal risk factors, and laboratory findings were analyzed. CD163 levels were measured and correlated with clinical outcomes. Results: CD163 concentrations were markedly higher in both EOS and LOS cohorts relative to the control group. In the LOS cohort, CD163 levels demonstrated a positive association with platelet count and an inverse relationship with hemoglobin concentrations. No significant gender differences in CD163 levels were observed. Conclusion: CD163 serves as a critical biomarker for the prompt identification of neonatal sepsis, with a threshold value set at ≥ 4.5%. Its use in clinical practice could enhance early diagnosis and treatment as well as reduction of neonatal morbidity and mortality. [ABSTRACT FROM AUTHOR]

Background: Acute tubular injury (ATI) is a common diagnosis on renal biopsy. There are no accepted parameters to assess the severity of injury or predict recovery. An objective histologic grading system would be of immense value in clinical practice. The macrophage response to injury involves the MI phenotype which is proinflammatory and M2 which is prorepair. The study of these macrophages could aid in studying the severity and the recovery. Materials and Methods: A total of 58 native kidney biopsies with features of ATI and a minimum follow-up of 12 weeks were graded into mild, moderate and severe, using scores for simplification, sloughing, and mitosis. These scores and the density of macrophages stained with CD68, CD163, and HLA-DR were correlated with serum creatinine at presentation and with recovery. The effect of chronicity index as measured by glomerulosclerosis, tubular atrophy, and interstitial fibrosis and of co-morbidities of age, hypertension, and diabetes on the recovery pattern was also studied. Results: All three histologic scores and the grades of ATI showed positive correlation with the serum creatinine level. The densities of CD 68 + and CD163 + macrophages also showed a significant correlation with serum creatinine level. However, none of these these histological features nor the macrophage densities predicted clinical recovery. Age >60 years, hypertension, diabetes, and chronicity score on biopsy were indicators of partial and delayed recovery. Conclusion: The histopathological semiquantitative scoring system can be used routinely to grade ATI. However none of the studied parameters predicted recovery. [ABSTRACT FROM AUTHOR]

Background: To investigate the role of CD47 expression and its relationship with tumor‐resident macrophages, specifically at the tumor margin, in patients with type II endometrial cancer. This study aims to elucidate whether CD47 could serve as a prognostic marker and to understand the dynamics between CD47 and macrophages, which could inform new therapeutic strategies. Methods: A retrospective cohort study was conducted involving 75 patients of type II endometrial. Immunohistochemical analysis was performed to assess CD47 expression and macrophage markers (CD68 and CD163). Results: The study found no direct correlation between CD47 expression levels and overall survival (p = 0.32), challenging its role as an independent prognostic marker in type II endometrial cancer. The higher expression of CD47 had significantly less incidence of endometrioid carcinoma G3 (p = 0.047). The negative correlation between CD47 H‐score and the density of CD68‐positive macrophages at tumor margin was statistically significant (p = 0.049). A high density of CD68‐positive macrophages at the tumor margin but a low density of CD163‐positive macrophages at the tumor margin were associated with poorer prognosis (p = 0.036). Conclusions: The complex interaction between CD47 and macrophages, particularly at the tumor margin, suggests new avenues for targeted therapy in type II endometrial cancer. [ABSTRACT FROM AUTHOR]

• Contraction frequency of the colon increases during LPS-induced systemic inflammation. • The gut-brain axis governs resting gut diameter during systemic inflammation. • Blocking the inhibitory enteric nervous system activity does not restore colonic motility. • Removing intestinal macrophages does not restore colonic motility. • Colonic motility during systemic interaction is regulated by systems additional to the enteric nervous system and intestinal macrophages. • Treatments for colonic dysmotility should consider gut-brain and gut immune cell interactions. The gastrointestinal tract is one of the main organs affected during systemic inflammation and disrupted gastrointestinal motility is a major clinical manifestation. Many studies have investigated the involvement of neuroimmune interactions in regulating colonic motility during localized colonic inflammation, i.e., colitis. However, little is known about how the enteric nervous system and intestinal macrophages contribute to dysregulated motility during systemic inflammation. Given that systemic inflammation commonly results from the innate immune response against bacterial infection, we mimicked bacterial infection by administering lipopolysaccharide (LPS) to rats and assessed colonic motility using ex vivo video imaging techniques. We utilized the Cx3cr1-Dtr rat model of transient depletion of macrophages to investigate the role of intestinal macrophages in regulating colonic motility during LPS infection. To investigate the role of inhibitory enteric neurotransmission on colonic motility following LPS, we applied the nitric oxide synthase inhibitor, Nω-nitro-L-arginine (NOLA). Our results confirmed an increase in colonic contraction frequency during LPS-induced systemic inflammation. However, neither the depletion of intestinal macrophages, nor the suppression of inhibitory enteric nervous system activity impacted colonic motility disruption during inflammation. This implies that the interplay between the enteric nervous system and intestinal macrophages is nuanced, and complex, and further investigation is needed to clarify their joint roles in colonic motility. [ABSTRACT FROM AUTHOR]

Porcine reproductive and respiratory syndrome (PRRS) is a globally prevalent contagious disease caused by the positive-strand RNA PRRS virus (PRRSV), resulting in substantial economic losses in the swine industry. Modifying the CD163 SRCR5 domain, either through deletion or substitution, can eff1ectively confer resistance to PRRSV infection in pigs. However, large fragment modifications in pigs inevitably raise concerns about potential adverse effects on growth performance. Reducing the impact of genetic modifications on normal physiological functions is a promising direction for developing PRRSV-resistant pigs. In the current study, we identified a specific functional amino acid in CD163 that influences PRRSV proliferation. Viral infection experiments conducted on Marc145 and PK-15CD163 cells illustrated that the mE535G or corresponding pE529G mutations markedly inhibited highly pathogenic PRRSV (HP-PRRSV) proliferation by preventing viral binding and entry. Furthermore, individual viral challenge tests revealed that pigs with the E529G mutation had viral loads two orders of magnitude lower than wild-type (WT) pigs, confirming effective resistance to HP-PRRSV. Examination of the physiological indicators and scavenger function of CD163 verified no significant differences between the WT and E529G pigs. These findings suggest that E529G pigs can be used for breeding PRRSV-resistant pigs, providing novel insights into controlling future PRRSV outbreaks. [ABSTRACT FROM AUTHOR]

Simple Summary: Fasciolosis is a parasitic disease of livestock causing important economic losses worldwide, and it is also a zoonosis. The treatment is based on the use of anthelmintic drugs, but the increase in resistance and the risk of drug residues in food make this approach no longer sustainable. Developing protective vaccines for the control of fasciolosis is postulated as an appropriate treatment, but a better knowledge of the host–parasite interaction is needed. The aim of the present study was to evaluate the hepatic lesions in sheep infected and reinfected with Fasciola hepatica during the acute and chronic stages of infection and the characterization of the hepatic inflammatory infiltrates using immunohistochemistry with CD3, Foxp3, iNOS, and CD163 antibodies. The most remarkable histopathological finding was the presence of large necrotic foci and/or hemorrhages adjacent to enlarged bile ducts containing adult parasites, suggesting flukes may have caused these lesions while feeding. In the literature, necrotic foci/hemorrhages are considered a consequence of parasite migration. In both the primoinfected and reinfected groups, and during acute and chronic stages of the infection, an increase in Foxp3 T cells with respect to uninfected controls and a poor expression of iNOS was found accompanied by a strong expression of CD163, suggesting a marked M2 activation of macrophages in the hepatic lesions. Fasciolosis is an important economic disease of livestock. There is a global interest in the development of protective vaccines since the current anthelmintic therapy is no longer sustainable. A better knowledge of the host–parasite interaction is needed to design effective vaccines. To date, few studies have evaluated host–parasite interaction by comparing infected and reinfected animals. The present study evaluates the microscopical hepatic lesions in sheep infected and reinfected with Fasciola hepatica during the acute and chronic stages of infection. The histopathological study revealed the presence of necrotizing foci (NF1) associated with larvae migration during the early stages of infection in the primoinfected (PI) and reinfected (RI) groups. In the late stages of infection of the PI group and at the early and late stages of infection in the RI groups, extensive necrotizing/hemorrhagic foci (NF2) were found in the vicinity of enlarged bile ducts, some containing adult flukes, suggesting parasites may have caused NF2 while feeding. The immunohistochemical study revealed an increase in Foxp3+ T cells in both PI and RI groups with respect to the UC group and in the infiltrates adjacent to NF1 in the RI groups with respect to the PI group, suggesting the F. hepatica induce Foxp3 T cell expansion to facilitate parasite survival. In addition, in both the PI and RI groups, and during acute and chronic stages of the infection, a poor expression of iNOS was found accompanied by a strong expression of CD163, suggesting a marked M2 activation of macrophages in the hepatic lesions, which may be related with healing processes, and it also may facilitate parasite survival. The main differences between PI and RI animals were the more severe infiltration of eosinophils and Foxp3+ T cells, whereas RI did not modify M2 activation of macrophages which occurs since the early stages of primoinfection. [ABSTRACT FROM AUTHOR]

Simple Summary: The manual assessment and identification of tumor-associated macrophages (TAMs) with a single marker limits a thorough analysis of their spatial distribution and density. We applied a digital workflow to compare the features of TAM populations identified by CD163 and CD206 and showed that these markers highlighted TAM populations with distinct clinical implications. The spatial distribution of CD163 TAMs and their interactions with tumor-infiltrating lymphocytes (TILs) refined the prognostic value in breast cancer. Conversely, CD206 TAMs may not have any unfavorable prognostic impact. Tumor-associated macrophages (TAMs) is a key element in the breast tumor microenvironment. CD163 and CD206 have been utilized for TAM identification, but the clinical implications of TAMs identified by these markers have not been thoroughly explored. This study conducted a comparative analysis of CD163 and CD206 TAMs using digital image analysis, focusing on their spatial distribution and prognostic significance in relation to tumor-infiltrating lymphocytes (TILs). Distinct clinico-pathological and prognostic characteristics were noted between the two types of TAMs. CD163 TAMs were linked to high-grade tumors (p = 0.006), whereas CD206 TAMs were associated with a higher incidence of nodal metastasis (p = 0.033). CD206 TAMs were predominantly found in the stroma, with more cases being stromal CD206-high (sCD206-high) than tumoral CD206-high (tCD206-high) (p = 0.024). Regarding prognostication, patients stratified according to stromal and tumoral densities of CD163 showed different disease-free survival (DFS) time. Specifically, those that were sCD163-low but tCD163-high exhibited the poorest DFS (chi-square = 10.853, p = 0.013). Furthermore, a high sCD163-to-stromal-TILs ratio was identified as an independent predictor of unfavorable survival outcomes (DFS: HR = 3.477, p = 0.018). The spatial distribution and interactions with TILs enhanced the prognostic value of CD163 TAMs, while CD206 TAMs appeared to have limited prognostic utility in breast cancer cases. [ABSTRACT FROM AUTHOR]

The impact of tumor microenvironment (TME) in influencing clinical response to first-line immune checkpoint inhibitor (ICI)-based treatment in advanced renal cell carcinoma (RCC) is unclear. Immunohistochemistry (IHC) could identify biomarkers related to immune checkpoints and immune cell population. This study retrospectively characterized TME from 28 RCC patients who received first line ICI-based therapy through IHC assessment of selected markers and explored preliminary evidence about their possible correlation with treatment efficacy. We found a significantly higher count of CD80+, CD163+ cells and their ratio in RCC with clear cell component compared to those without clear cell features; additionally, patients with metastatic disease at diagnosis were associated with higher expression of CD163+ cells, while higher count of CD4+ cells and CD4+/CD8+ ratio were found in RCC with sarcomatoid features. Patients achieving partial or complete response were associated with lower expression of CD163+ cells (median 28 vs 47; p = 0.049). Furthermore, lower expression of CD163+ was associated with better PFS (median PFS 20.0 vs 4.7 months; HR 0.22 p = 0.011) and OS (median OS NR vs 14.4 months; HR 0.28 p = 0.036). A longer OS was reported in PD-L1 CPS negative patients (median OS NR vs 11.8 months; HR 0.20 p = 0.024). High infiltration of CD163+ macrophages, who typically present “anti-inflammatory” M2-like phenotype, could identify a subgroup of patients with poor survival after receiving first-line ICI. [ABSTRACT FROM AUTHOR]

Background and Objectives: Inflammatory proteins and their prognostic value in patients with carotid artery stenosis (CAS) have not been adequately studied. Herein, we identified CAS-specific biomarkers from a large pool of inflammatory proteins and assessed the ability of these biomarkers to predict adverse events in individuals with CAS. Materials and Methods: Samples of blood were prospectively obtained from 336 individuals (290 with CAS and 46 without CAS). Plasma concentrations of 29 inflammatory proteins were determined at recruitment, and the patients were followed for 24 months. The outcome of interest was a major adverse cardiovascular event (MACE; composite of stroke, myocardial infarction, or death). The differences in plasma protein concentrations between patients with vs. without a 2-year MACE were determined using the independent t-test or Mann–Whitney U test to identify CAS-specific prognostic biomarkers. Kaplan–Meier and Cox proportional hazards analyses with adjustment for baseline demographic and clinical characteristics were performed to assess the prognostic value of differentially expressed inflammatory proteins in predicting a 2-year MACE in patients with CAS. Results: The mean age of the cohort was 68.8 (SD 10.2) years and 39% were female. The plasma concentrations of two inflammatory proteins were significantly higher in individuals with a 2-year MACE relative to those without a 2-year MACE: IL-6 (5.07 (SD 4.66) vs. 3.36 (SD 4.04) pg/mL, p = 0.03) and CD163 (233.825 (SD 230.306) vs. 159.673 (SD 175.669) pg/mL, p = 0.033). Over a follow-up period of 2 years, individuals with elevated levels of IL-6 were more likely to develop MACE (HR 1.269 (95% CI 1.122–1.639), p = 0.042). Similarly, over a 2-year period, patients with high levels of CD163 were more likely to develop MACE (HR 1.413 (95% CI 1.022–1.954), p = 0.036). Conclusions: The plasma levels of inflammatory proteins IL-6 and CD163 are independently associated with adverse outcomes in individuals with CAS. These CAS-specific prognostic biomarkers may assist in the risk stratification of patients at an elevated risk of a MACE and subsequently guide further vascular evaluation, specialist referrals, and aggressive medical/surgical management, thereby improving outcomes for patients with CAS. [ABSTRACT FROM AUTHOR]

Background and aimHead and neck paragangliomas (HNPGN) are tumours that carry significant morbidity The role of the stroma in the pathogenesis of HNPGN is not completely understood. This study explores the profile of fibroblasts and macrophages in HNPGN.MethodsTen patients undergoing HNPGN surgery were recruited. CD68 and CD163 immunohistochemistry was performed for macrophage analysis; CD90 and podoplanin (PDPN) expression was examined to identify fibroblasts. RT-qPCR was performed on HNPGN tissue for macrophage- and fibroblast-associated molecules. Fibroblast cultures were established from HNPGN were analysed by RT-qPCR and flowcytometry. Confocal microscopy for MCT1 and MCT4 was performed in HNPGN.ResultsCD68 and CD163 expressing macrophages were noted in HNPGN. CD90 and PDPN expressing cells were present in HNPGN. RT-qPCR analysis showed expression of phenotypic and functional macrophage- and fibroblast-associated molecules in HNPGN. RT-qPCR analysis of fibroblasts cultured from HNPGN confirmed the expression of several molecules including PDPN at comparable levels to healthy tissue fibroblasts. Expression of FAP, MCT-1, insulin receptor (CD220) and insulin growth factor receptor-2 (CD222) was noted on HNPGN derived fibroblasts on flowcytometry. MCT1 and MCT4 were expressed in HNPGN tumour cells and stromal macrophages in-situ.ConclusionFibroblasts and macrophages are present in the HNPGN tumour microenvironment, and several macrophage and fibroblast functional markers are expressed in HNPGN. Macrophages in HNPGN tissue express metabolic markers MCT1 and MCT4. Further analysis of the fibroblast and macrophage function in HNPGN will improve our understanding of their potential roles in tumour pathogenesis.

IntroductionBlood-based diagnostics and prognostics in sporadic Alzheimer's disease (AD) are important for identifying at-risk individuals for therapeutic interventions.MethodsIn three stages, a total of 34 leukocyte antigens were examined by flow cytometry immunophenotyping. Data were analyzed by logistic regression and receiver operating characteristic (ROC) analyses.ResultsWe identified leukocyte markers differentially expressed in the patients with AD. Pathway analysis revealed a complex network involving upregulation of complement inhibition and downregulation of cargo receptor activity and Aβ clearance. A proposed panel including four leukocyte markers - CD11c, CD59, CD91, and CD163 - predicts patients' PET Aβ status with an area under the curve (AUC) of 0.93 (0.88 to 0.97). CD163 was the top performer in preclinical models. These findings have been validated in two independent cohorts.ConclusionOur finding of changes on peripheral leukocyte surface antigens in AD implicates the deficit in innate immunity. Leukocyte-based biomarkers prove to be both sensitive and practical for AD screening and diagnosis.

Abstract Background Tumor-associated macrophages (TAMs) are a prominent immune subpopulation in the tumor microenvironment that could potentially serve as therapeutic targets for breast cancer. Thus, it is important to characterize this cell population across different tumor subtypes including patterns of association with demographic and prognostic factors, and breast cancer outcomes. Methods We investigated CD163+ macrophages in relation to clinicopathologic variables and breast cancer outcomes in the Women’s Circle of Health Study and Women’s Circle of Health Follow-up Study populations of predominantly Black women with breast cancer. We evaluated 611 invasive breast tumor samples (507 from Black women, 104 from White women) with immunohistochemical staining of tissue microarray slides followed by digital image analysis. Multivariable Cox proportional hazards models were used to estimate hazard ratios for overall survival (OS) and breast cancer-specific survival (BCSS) for 546 cases with available survival data (median follow-up time 9.68 years (IQR: 7.43–12.33). Results Women with triple-negative breast cancer showed significantly improved OS in relation to increased levels of tumor-infiltrating CD163+ macrophages in age-adjusted (Q3 vs. Q1: HR = 0.36; 95% CI 0.16–0.83) and fully adjusted models (Q3 vs. Q1: HR = 0.30; 95% CI 0.12–0.73). A similar, but non-statistically significant, association was observed for BCSS. Macrophage infiltration in luminal and HER2+ tumors was not associated with OS or BCSS. In a multivariate regression model that adjusted for age, subtype, grade, and tumor size, there was no significant difference in CD163+ macrophage density between Black and White women (RR = 0.88; 95% CI 0.71–1.10). Conclusions In contrast to previous studies, we observed that higher densities of CD163+ macrophages are independently associated with improved OS and BCSS in women with invasive triple-negative breast cancer. Trial registration Not applicable.

Background: Tumor-associated macrophages (TAMs) are a prominent immune subpopulation in the tumor microenvironment that could potentially serve as therapeutic targets for breast cancer. Thus, it is important to characterize this cell population across different tumor subtypes including patterns of association with demographic and prognostic factors, and breast cancer outcomes. Methods: We investigated CD163+ macrophages in relation to clinicopathologic variables and breast cancer outcomes in the Women's Circle of Health Study and Women's Circle of Health Follow-up Study populations of predominantly Black women with breast cancer. We evaluated 611 invasive breast tumor samples (507 from Black women, 104 from White women) with immunohistochemical staining of tissue microarray slides followed by digital image analysis. Multivariable Cox proportional hazards models were used to estimate hazard ratios for overall survival (OS) and breast cancer-specific survival (BCSS) for 546 cases with available survival data (median follow-up time 9.68 years (IQR: 7.43–12.33). Results: Women with triple-negative breast cancer showed significantly improved OS in relation to increased levels of tumor-infiltrating CD163+ macrophages in age-adjusted (Q3 vs. Q1: HR = 0.36; 95% CI 0.16–0.83) and fully adjusted models (Q3 vs. Q1: HR = 0.30; 95% CI 0.12–0.73). A similar, but non-statistically significant, association was observed for BCSS. Macrophage infiltration in luminal and HER2+ tumors was not associated with OS or BCSS. In a multivariate regression model that adjusted for age, subtype, grade, and tumor size, there was no significant difference in CD163+ macrophage density between Black and White women (RR = 0.88; 95% CI 0.71–1.10). Conclusions: In contrast to previous studies, we observed that higher densities of CD163+ macrophages are independently associated with improved OS and BCSS in women with invasive triple-negative breast cancer. Trial registration Not applicable. [ABSTRACT FROM AUTHOR]

Dysregulation of iron metabolism has been associated with impaired chronic wound healing. However, changes in iron metabolism have yet to be reported in pressure injuries, a type of chronic wound. In this study, we aimed to investigate changes in iron metabolism and associated regulatory mechanisms in pressure injuries. We collected tissue biopsies and data from 20 consenting stage IV‐pressure injuries patients and 5 non‐pressure injuries patients hospitalised at the Affiliated Hospital of Qingdao University between March 2021 and June 2021. In addition, we measured the iron content by inductively coupled plasma mass spectrometry and Prussian blue staining in deep tissue pressure injury mouse models. An Enzyme‐linked immune sorbent assay measured the expression of ferritin, ferroportin‐1 and transferrin. Immunofluorescence staining, high‐throughput transcriptome sequencing, Western blot and RT‐qPCR further analysed the fundamental mechanisms regulating iron metabolism. In this study, we observed numerous inflammatory cells infiltrating the marginal tissues of stage IV pressure injury patients and in deep tissue pressure injury models. The expression levels of pro‐inflammatory factors, such as inducible nitric oxide synthase and interleukin‐6, were significantly increased (p < 0.05). The iron level was proportional to the degree of progression, with the most significant change appearing on the third day in deep tissue pressure injury models (p < 0.05). Enzyme‐linked immune sorbent assay results suggested abnormal gene expression was related to iron metabolism, including a substantial increase in ferritin and a significant decrease in the expression of ferroportin‐1 (p < 0.05). In addition, immunofluorescence staining and Western blot showed that the expression of macrophage membrane receptor CD163 was abnormally elevated (p < 0.05). Both high‐throughput transcriptome sequencing and qRT‐PCR results suggested aberrant expression of the CD163/Homx‐1‐mediated signalling pathway. Dysfunctional iron metabolism was suggested to be related to the aberrant CD163/Homx‐1 signalling pathway in deep tissue pressure injury models. [ABSTRACT FROM AUTHOR]

Early evidence suggests a strong impact of tumour-infiltrating lymphocytes (TILs) on both the prognosis and clinical behaviour of ovarian cancer. Proven associations, however, have not yet translated to successful immunotherapies and further work in the field is urgently needed. We aimed to analyse the tumour microenvironment of a well-characterised cohort of ovarian cancer samples. Tumour markers were selected owing to their comparative underrepresentation in the current literature. Paraffin-embedded, formalin-fixed tumour tissue blocks of 138 patients representative of the population and including early stage disease were identified, stained for CD3, CD20, CD68 and CD163 and analysed for both the stromal and intertumoral components. Data were statistically analysed in relation to clinical details, histological subtype, borderline vs. malignant status, survival and management received. Mean stromal CD3, total CD3 count, mean stromal CD20 and total CD20 count all correlated negatively with survival. Malignant ovarian tumours consistently demonstrated significantly higher infiltration of all analysed immune cells than borderline tumours. Assessment of the stromal compartment produced a considerably higher proportion of significant results when compared to the intra-tumoural infiltrates. Customary assessment of solely intra-tumoural cells in advanced stage disease patients undergoing primary debulking surgery should be challenged, with recommendations for future scoring systems provided. [ABSTRACT FROM AUTHOR]

AIM: To investigate the expression of inducible nitric oxide synthase （iNOS） and CD163 in periapical tissues at varying stages of human chronic apical periodotitis （CAP）. METHODS: Forty-five voluntary samples were collected and categorized into three groups based on the degree of CAP: healthy control group （n=15）, chronic apical abscess group （n=15）, and periapical cyst group （n=15）. Double immunofluorescence staining was employed to examine the expression of CD68+-iNOS+ and CD68+-CD163+ cells in periapical tissues. RESULTS: （1） The densities of CD68+- iNOS+ and CD68+-CD163+ cells showed significant differences among CAP groups （P<0. 01）. （2） The density of CD68+- iNOS+ cells in chronic apical abscess group was significantly higher than that in periapical cyst group （P<0. 01）. However, there was no significant difference in the density of CD68+-CD163+ cells between chronic apical abscess group and periapical cyst group （P>0. 05）. （3） The ratio of CD68+-iNOS+/CD68+-CD163+ was significantly higher in chronic apical abscess group compared with periapical cyst group （P<0. 01）, while there was no significant difference in this ratio between chronic apical abscess group and healthy control group（ P>0. 05）. CONCLUSION: The expression ratio of CD68+- iNOS+/CD68+-CD163+ between chronic apical abscess and periapical cyst groups differed. Modulating the proportion of CD68+-iNOS+/CD68+-CD163+ may be involved in the development of CAP at various stages. [ABSTRACT FROM AUTHOR]

Genetically modified pigs play a critical role in mimicking human diseases, xenotransplantation, and the development of pigs resistant to viral diseases. The use of programmable endonucleases, including the CRISPR/Cas9 system, has revolutionized the generation of genetically modified pigs. This study evaluates the efficiency of electroporation of oocytes prior to fertilization in generating edited gene embryos for different models. For single gene editing, phospholipase C zeta (PLC ζ) and fused in sarcoma (FUS) genes were used, and the concentration of sgRNA and Cas9 complexes was optimized. The results showed that increasing the concentration resulted in higher mutation rates without affecting the blastocyst rate. Electroporation produced double knockouts for the TPC1/TPC2 genes with high efficiency (79 %). In addition, resistance to viral diseases such as PRRS and swine influenza was achieved by electroporation, allowing the generation of double knockout embryo pigs (63 %). The study also demonstrated the potential for multiple gene editing in a single step using electroporation, which is relevant for xenotransplantation. The technique resulted in the simultaneous mutation of 5 genes (GGTA1, B4GALNT2, pseudo B4GALNT2, CMAH and GHR). Overall, electroporation proved to be an efficient and versatile method to generate genetically modified embryonic pigs, offering significant advances in biomedical and agricultural research, xenotransplantation, and disease resistance. Electroporation led to the processing of numerous oocytes in a single session using less expensive equipment. We confirmed the generation of gene-edited porcine embryos for single, double, or quintuple genes simultaneously without altering embryo development to the blastocyst stage. The results provide valuable insights into the optimization of gene editing protocols for different models, opening new avenues for research and applications in this field. • Oocyte electroporation is an efficient method for generating single, double, and multiple knockout porcine embryos. • Electroporation does not interfere with early embryonic development. • Electroporation offers the potential to edit multiple genes simultaneously in a single step. [ABSTRACT FROM AUTHOR]

Acute kidney injury (AKI) is a common finding in hospitalized patients, particularly those who are critically ill. The development of AKI is associated with several adverse outcomes including mortality, morbidity, progression to chronic kidney disease, and an increase in healthcare expenditure. Despite the well-established negative impact of AKI and rigorous efforts to better define, identify, and implement targeted therapies, the overall approach to the treatment of AKI continues to principally encompass supportive measures. This enduring challenge is primarily due to the heterogeneous nature of insults that activate many independent and overlapping molecular pathways. Consequently, it is evident that the identification of common mechanisms that mediate the pathogenesis of AKI, independent of etiology and engaged pathophysiological pathways, is of paramount importance and could lead to the identification of novel therapeutic targets. To better distinguish the commonly modulated mechanisms of AKI, we explored the transcriptional characteristics of human kidney biopsies from patients with acute tubular necrosis (ATN), and acute interstitial nephritis (AIN) using a NanoString inflammation panel. Subsequently, we used publicly available single-cell transcriptional resources to better interpret the generated transcriptional findings. Our findings identify robust acute kidney injury (AKI-induced) developmental reprogramming of macrophages (MΦ) with the expansion of C1Q+, CD163+ MΦ that is independent of the etiology of AKI and conserved across mouse and human species. These results would expand the current understanding of the pathophysiology of AKI and potentially offer novel targets for additional studies to enhance the translational transition of AKI research. NEW & NOTEWORTHY: Our findings identify robust acute kidney injury (AKI)-induced developmental reprogramming of macrophages (MΦ) with the expansion of C1Q+, CD163+ MΦ that is independent of the etiology of AKI and conserved across mouse and human species. [ABSTRACT FROM AUTHOR]

It is aimed to determine expression of programmed cell death-1 (PD-1), programmed cell death ligand-1 (PD-L1), CD163 and CD14 in diffuse large B-cell lymphomas (DLBCL), and whether these markers may predict prognosis in DLBCL cases. A total of 52 nodal DLBCL, NOS cases with no known extranodal involvement at the time of diagnosis were evaluated. PD-1, PD-L1, CD163, and CD14 were studied by immunohistochemistry. The relationships between the results and clinical and laboratory prognostic markers were investigated. It was observed that patients with PD-1 expression < 5 positive cells/HPF had worse overall survival. No significant relationship was found between survival and PD-L1, CD163 and CD14 expressions. In addition, cases that are > 60 years of age, that have Eastern Cooperative Oncology Group (ECOG) performance score ≥ 2, stage IV disease, high International Prognostic Index score score (≥ 3), elevation of LDH, low albumin level, low hemoglobin level, low peripheral blood lymphocyte count, high peripheral blood neutrophil/lymphocyte ratio, high peripheral blood platelet/lymphocyte ratio were found to have worse overall survival. It was concluded that in patients with low number of PD-1 positive tumor-infiltrating lymphocytes have low survival rates and therefore PD-1 expression may be useful in indicating prognosis. [ABSTRACT FROM AUTHOR]

Coronavirus disease (COVID-19) begins with upper airway symptoms but proceeds in a significant proportion of patients to life-threatening infection of the lower respiratory tract, where an exuberant inflammatory response, edema, and adverse parenchymal remodeling impair gas exchange. Respiratory failure is caused initially by flooding of the airspaces with plasma exudate, sloughed epithelium, and inflammatory cells. For many patients with COVID-19, this acute phase has been observed to give way to a prolonged course of acute respiratory distress syndrome, and a significant proportion of patients go on to develop fibroproliferative remodeling of the lung parenchyma, which lengthens the duration of respiratory impairment and mechanical ventilation. Monocyte-derived macrophages have previously been implicated in the fibrotic phase of lung injury in multiple models. From several recent studies that used single-cell genomic techniques, a profile of the transcriptomic state of COVID-19 lung macrophages has emerged. Linkages have been made between these macrophages, which are monocyte-derived and CD163+, and profibrotic macrophages found in other contexts, including animal models of fibrosis and idiopathic pulmonary fibrosis. Here, emerging concepts of macrophage profibrotic function in COVID-19 are highlighted with a focus on gaps in knowledge to be addressed by future research.

Abstract Background Triple-negative breast cancer (TNBC) has been documented as the most aggressive subtype of breast cancer. This study aimed to analyze antitumor and protumor immune activities, and their ratios as significant prognostic biomarkers in metastatic TNBC (mTNBC). Methods A multicenter cohort study was conducted among 103 de novo mTNBC patients. The expression of CD8 and CD163 was evaluated using immunohistochemistry staining, CD4 and FOXP3 using double-staining immunohistochemistry, and PD-L1 using immunohistochemistry and RT-PCR. Results Multivariate analysis revealed that high CD4/FOXP3 (HR 1.857; 95% CI 1.049–3.288; p = 0.034) and the CD8/CD163 ratio (HR 2.089; 95% CI 1.174–3.717; p = 0.012) yield significantly improved 1 year overall survival (OS). Kaplan–Meier analysis showed that high levels of CD4 (p = 0.023), CD8 (p = 0.043), CD4/FOXP3 (p = 0.016), CD8/FOXP3 (p = 0.005), CD8/CD163 (p = 0.005) ratios were significantly associated with higher rate of 1 year OS. Furthermore, 1 year OS was directly correlated with antitumor CD4 (R = 0.233; p = 0.018) and CD8 (R = 0.219; p = 0.026) and was indirectly correlated with protumor CD163 and FOXP3 through CD4/FOXP3 (R = 0.282; p = 0.006), CD4/CD163 (R = 0.239; p = 0.015), CD8/FOXP3 (R = 0.260; p = 0.008), and CD8/CD163 (R = 0.258; p = 0.009). Conclusion This is the first study to demonstrate that high levels of CD4/FOXP3 and CD8/CD163 significantly improved the 1 year OS in de novo mTNBC patients. Thus, we recommend the application of these markers as prognosis determination and individual treatment decision.

Abstract Background Identification of the causes of stroke of undetermined etiology, specifically cardioembolism (CE) and non-CE causes, can inform treatment planning and prognosis prediction. The objective of this study was to analyze the disparities in thrombus composition, particularly Semaphorin-7A (Sema7A) and CD163, between patients diagnosed with large-artery atherosclerosis (LAA) and those with CE, and to investigate their potential association with prognosis. Methods Thrombi were collected from patients who underwent mechanical thrombectomy at two hospitals. The patients were categorized into two groups: LAA and CE. We compared the levels of Sema7A and CD163 between these groups and analyzed their relationships with stroke severity, hemorrhagic transformation and prognosis. Results The study involved a total of 67 patients. Sema7A expression was found to be significantly higher in the CE group compared to LAA (p 0.05). However, both Sema7A (OR, 2.017; 95% CI, 1.301–3.518; p = 0.005) and CD163 (OR, 2.283; 95% CI, 1.252–5.724; p = 0.03) were associated with the poor prognosis for stroke, after adjusting for stroke severity. Conclusion This study highlights that CE thrombi exhibited higher levels of Sema7A expression compared to LAA thrombi. Moreover, we found a positive correlation between Sema7A/CD163 levels and the poor prognosis of patients with acute ischemic stroke.

Abstract Alpha-1-antitrypsin deficiency (AATD) is a genetic disorder associated with a 5–tenfold decrease in lung levels of alpha-1-antitrypsin (AAT) and an increased risk for obstructive lung disease. α-defensins are cationic broad-spectrum cytotoxic and pro-inflammatory peptides found in the azurophilic granules of neutrophils. The concentration of α-defensins is less than 30 nM in the bronchoalveolar lavage fluid of healthy controls but is up to 6 μM in AATD individuals with significant lung function impairment. Alveolar macrophages are generally classified into pro-inflammatory (M1) or anti-inflammatory (M2) subsets that play distinct roles in the initiation and resolution of inflammation. Therefore, monocyte-macrophage differentiation should be tightly controlled to maintain lung integrity. In this study, we determined the effect of α-defensins on monocyte-macrophage differentiation and identified the molecular mechanism of this effect. The results of this study demonstrate that 2.5 μM of α-defensins inhibit the phosphorylation of ERK1/2 and STAT3 and suppress the expression of M2 macrophage markers, CD163 and CD206. In addition, a scratch assay shows that the high concentration of α-defensins inhibits cell movement by ~ 50%, and the phagocytosis assay using flow cytometry shows that α-defensins significantly reduce the bacterial phagocytosis rate of monocyte-derived macrophages (MDMs). To examine whether exogenous AAT is able to alleviate the inhibitory effect of α-defensins on macrophage function, we incubated MDMs with AAT prior to α-defensin treatment and demonstrate that AAT improves the migratory ability and phagocytic ability of MDMs compared with MDMs incubated only with α-defensins. Taken together, this study suggests that a high concentration of α-defensins inhibits the activation of ERK/STAT3 signaling, negatively regulates the expression of M2 macrophage markers, and impairs innate immune function of macrophages.

African Swine Fever Virus (ASFV), resulting in strain-dependent vascular pathology, leading to hemorrhagic fever, is an important pathogen in swine. The pathogenesis of ASFV is determined by the array and spatial distribution of susceptible cells within the host. In this study, the replication characteristics of ASFV genotype I E70 (G1-E70) and ASFV genotype II Belgium 2018/1 (G2-B18) in the environment of small veins were investigated in an established vein explant model. Immunofluorescence staining analysis revealed that perivenous macrophages (CD163+ cells) were widely distributed in the explant, with most of them (approximately 2–10 cells/0.03 mm2) being present close to the vein (within a radius of 0–348 µm). Upon inoculation with G1-E70 and G2-B18, we observed an increase in the quantity of cells testing positive for viral antigens over time. G1-E70 replicated more efficiently than G2-B18 in the vein explants (7.6-fold for the ear explant at 72 hpi). The majority of ASFV+ cells were CD163+, indicating that macrophages are the primary target cells. Additional identification of cells infected with ASFV revealed the presence of vimentin+, CD14+, and VWF+ cells, demonstrating the cellular diversity and complexity associated with ASFV infection. By the use of this new vein explant model, the susceptibility of vascular and perivascular cells to an ASFV infection was identified. With this model, it will be possible now to conduct more functional analyses to get better insights into the pathogenesis of ASFV-induced hemorrhages.

Soluble CD163 (sCD163) is a circulating inflammatory mediator, indicative of acute and chronic, systemic and non-systemic inflammatory conditions. It is the cleavage outcome, consisting of almost the entire extracellular domain, of the CD163, a receptor expressed in monocytic lineages. Its expression is proportional to the abundance of CD163+ macrophages. Various mechanisms trigger the shedding of the CD163 receptor or the accumulation of CD163-expressing macrophages, inducing the sCD163 concentration in the circulation and bodily fluids. The activities of sCD163 range from hemoglobin (Hb) scavenging, macrophage marker, decoy receptor for cytokines, participation in immune defense mechanisms, and paracrine effects in various tissues, including the endothelium. It is an established marker of macrophage activation and thus participates in many diseases, including chronic inflammatory conditions, such as atherosclerosis, asthma, and rheumatoid arthritis; acute inflammatory conditions, such as sepsis, hepatitis, and malaria; insulin resistance; diabetes; and tumors. The sCD163 levels have been correlated with the severity, stage of the disease, and clinical outcome for many of these conditions. This review article summarizes the expression and role of sCD163 and its precursor protein, CD163, outlines the sCD163 generation mechanisms, the biological activities, and the known underlying molecular mechanisms, with an emphasis on its impact on the endothelium and its contribution in the pathophysiology of human diseases.

CD163, a scavenger receptor with anti-inflammatory function expressed exclusively on monocytes/macrophages, is dysregulated in cases of diabetes complications. This study aimed to characterize circulating CD163+ monocytes in the presence (D+Comps) or absence (D−Comps) of diabetes-related complications. RNA-sequencing and mass cytometry were conducted on CD163+ monocytes in adults with long-duration diabetes and D+Comps or D−Comps. Out of 10,868 differentially expressed genes identified between D+Comps and D−Comps, 885 were up-regulated and 190 were down-regulated with a ≥ 1.5-fold change. In D+Comps, ‘regulation of centrosome cycle’ genes were enriched 6.7-fold compared to the reference genome. MIR27A, MIR3648-1, and MIR23A, the most up-regulated and CD200R1, the most down-regulated gene, were detected in D+Comps from the list of 75 ‘genes of interest’. CD163+ monocytes in D+Comps had a low proportion of recruitment markers CCR5, CD11b, CD11c, CD31, and immune regulation markers CD39 and CD86. A gene–protein network identified down-regulated TLR4 and CD11b as ‘hub-nodes’. In conclusion, this study reports novel insights into CD163+ monocyte dysregulation in diabetes-related complications. Enriched centrosome cycle genes and up-regulated miRNAs linked to apoptosis, coupled with down-regulated monocyte activation, recruitment, and immune regulation, suggest functionally distinct CD163+ monocytes in cases of diabetes complications. Further investigation is needed to confirm their role in diabetes-related tissue damage.

Background: Identification of the causes of stroke of undetermined etiology, specifically cardioembolism (CE) and non-CE causes, can inform treatment planning and prognosis prediction. The objective of this study was to analyze the disparities in thrombus composition, particularly Semaphorin-7A (Sema7A) and CD163, between patients diagnosed with large-artery atherosclerosis (LAA) and those with CE, and to investigate their potential association with prognosis. Methods: Thrombi were collected from patients who underwent mechanical thrombectomy at two hospitals. The patients were categorized into two groups: LAA and CE. We compared the levels of Sema7A and CD163 between these groups and analyzed their relationships with stroke severity, hemorrhagic transformation and prognosis. Results: The study involved a total of 67 patients. Sema7A expression was found to be significantly higher in the CE group compared to LAA (p < 0.001). Conversely, no statistically significant differences were observed for CD163 between the groups. The presence of Sema7A/CD163 did not show any associations with stroke severity or hemorrhagic transformation (all p > 0.05). However, both Sema7A (OR, 2.017; 95% CI, 1.301–3.518; p = 0.005) and CD163 (OR, 2.283; 95% CI, 1.252–5.724; p = 0.03) were associated with the poor prognosis for stroke, after adjusting for stroke severity. Conclusion: This study highlights that CE thrombi exhibited higher levels of Sema7A expression compared to LAA thrombi. Moreover, we found a positive correlation between Sema7A/CD163 levels and the poor prognosis of patients with acute ischemic stroke. [ABSTRACT FROM AUTHOR]

Patients with Alzheimer's disease (AD) often present with imaging features indicative of small-vessel injury, among which, white-matter hyperintensities (WMHs) are the most prevalent. However, the underlying mechanism of the association between AD and small-vessel injury is still obscure. The aim of this study is to investigate the mechanism of small-vessel injury in AD. Differential gene expression analyses were conducted to identify the genes related to WMHs separately in mild cognitive impairment (MCI) and cognitively normal (CN) subjects from the ADNI database. The WMH-related genes identified in patients with MCI were considered to be associated with small-vessel injury in early AD. Functional enrichment analyses and a protein–protein interaction (PPI) network were performed to explore the pathway and hub genes related to the mechanism of small-vessel injury in MCI. Subsequently, the Boruta algorithm and support vector machine recursive feature elimination (SVM-RFE) algorithm were performed to identify feature-selection genes. Finally, the mechanism of small-vessel injury was analyzed in MCI from the immunological perspectives; the relationship of feature-selection genes with various immune cells and neuroimaging indices were also explored. Furthermore, 5×FAD mice were used to demonstrate the genes related to small-vessel injury. The results of the logistic regression analyses suggested that WMHs significantly contributed to MCI, the early stage of AD. A total of 276 genes were determined as WMH-related genes in patients with MCI, while 203 WMH-related genes were obtained in CN patients. Among them, only 15 genes overlapped and were thus identified as the crosstalk genes. By employing the Boruta and SVM-RFE algorithms, CD163, ALDH3B1, MIR22HG, DTX2, FOLR2, ALDH2, and ZNF23 were recognized as the feature-selection genes linked to small-vessel injury in MCI. After considering the results from the PPI network, CD163 was finally determined as the critical WMH-related gene in MCI. The expression of CD163 was correlated with fractional anisotropy (FA) values in regions that are vulnerable to small-vessel injury in AD. The immunostaining and RT-qPCR results from the verifying experiments demonstrated that the indicators of small-vessel injury presented in the cortical tissue of 5×FAD mice and related to the upregulation of CD163 expression. CD163 may be the most pivotal candidates related to small-vessel injury in early AD. [ABSTRACT FROM AUTHOR]

Simple Summary: While tumor-associated macrophages (TAMs) are known to be associated with a poor prognosis in breast cancer (BC) in general, how they influence different BC subtypes has remained poorly studied. Here, we investigated the prognostic value of M2-like TAMs (CD163+) that mediate several pro-tumoral functions, and all TAMs (CD68+) in a patient cohort of 278 non-metastatic BC cases, half of which were HER2+. Our results indicate that M2-like TAMs were associated with a poor outcome in HER2+ BC, in which a high CD163+ TAM count was independently associated with an inferior outcome regardless of hormone receptor status and the use of adjuvant trastuzumab. In summary, our results suggest that the prognostic value of M2-like TAMs is especially significant in HER2+ BC; these patients might benefit from combination treatments that include therapies targeting macrophage function. Tumor-associated macrophages (TAMs) are associated with a poor outcome in breast cancer (BC), but their prognostic value in different BC subtypes has remained somewhat unclear. Here, we investigated the prognostic value of M2-like TAMs (CD163+) and all TAMs (CD68+) in a patient cohort of 278 non-metastatic BC patients, half of whom were HER2+ (n = 139). The survival endpoints investigated were overall survival (OS), breast cancer-specific survival (BCSS) and disease-free survival (DFS). In the whole patient cohort (n = 278), a high CD163+ TAM count and a high CD68+ TAM count were associated with a worse outcome (p ≤ 0.023). In HER2+ BC, a high CD163+ TAM count was an independent factor for a poor prognosis across all the investigated survival endpoints (p < 0.001). The prognostic effect was evident in both the HER2+/hormone receptor-positive (p < 0.001) and HER2+/hormone receptor-negative (p ≤ 0.012) subgroups and regardless of the provision of adjuvant trastuzumab (p ≤ 0.002). In HER2-negative BC, the CD163+ TAM count was not significantly associated with survival. These results suggest that a high CD163+ TAM count predicts an inferior outcome, especially in HER2+ BC patients, and as adjuvant trastuzumab did not overcome the poor prognostic effect, combination treatments including therapies targeting the macrophage function could represent an effective therapeutic approach in HER2+ BC. [ABSTRACT FROM AUTHOR]

Background: Triple-negative breast cancer (TNBC) has been documented as the most aggressive subtype of breast cancer. This study aimed to analyze antitumor and protumor immune activities, and their ratios as significant prognostic biomarkers in metastatic TNBC (mTNBC). Methods: A multicenter cohort study was conducted among 103 de novo mTNBC patients. The expression of CD8 and CD163 was evaluated using immunohistochemistry staining, CD4 and FOXP3 using double-staining immunohistochemistry, and PD-L1 using immunohistochemistry and RT-PCR. Results: Multivariate analysis revealed that high CD4/FOXP3 (HR 1.857; 95% CI 1.049–3.288; p = 0.034) and the CD8/CD163 ratio (HR 2.089; 95% CI 1.174–3.717; p = 0.012) yield significantly improved 1 year overall survival (OS). Kaplan–Meier analysis showed that high levels of CD4 (p = 0.023), CD8 (p = 0.043), CD4/FOXP3 (p = 0.016), CD8/FOXP3 (p = 0.005), CD8/CD163 (p = 0.005) ratios were significantly associated with higher rate of 1 year OS. Furthermore, 1 year OS was directly correlated with antitumor CD4 (R = 0.233; p = 0.018) and CD8 (R = 0.219; p = 0.026) and was indirectly correlated with protumor CD163 and FOXP3 through CD4/FOXP3 (R = 0.282; p = 0.006), CD4/CD163 (R = 0.239; p = 0.015), CD8/FOXP3 (R = 0.260; p = 0.008), and CD8/CD163 (R = 0.258; p = 0.009). Conclusion: This is the first study to demonstrate that high levels of CD4/FOXP3 and CD8/CD163 significantly improved the 1 year OS in de novo mTNBC patients. Thus, we recommend the application of these markers as prognosis determination and individual treatment decision. [ABSTRACT FROM AUTHOR]

Alpha-1-antitrypsin deficiency (AATD) is a genetic disorder associated with a 5–tenfold decrease in lung levels of alpha-1-antitrypsin (AAT) and an increased risk for obstructive lung disease. α-defensins are cationic broad-spectrum cytotoxic and pro-inflammatory peptides found in the azurophilic granules of neutrophils. The concentration of α-defensins is less than 30 nM in the bronchoalveolar lavage fluid of healthy controls but is up to 6 μM in AATD individuals with significant lung function impairment. Alveolar macrophages are generally classified into pro-inflammatory (M1) or anti-inflammatory (M2) subsets that play distinct roles in the initiation and resolution of inflammation. Therefore, monocyte-macrophage differentiation should be tightly controlled to maintain lung integrity. In this study, we determined the effect of α-defensins on monocyte-macrophage differentiation and identified the molecular mechanism of this effect. The results of this study demonstrate that 2.5 μM of α-defensins inhibit the phosphorylation of ERK1/2 and STAT3 and suppress the expression of M2 macrophage markers, CD163 and CD206. In addition, a scratch assay shows that the high concentration of α-defensins inhibits cell movement by ~ 50%, and the phagocytosis assay using flow cytometry shows that α-defensins significantly reduce the bacterial phagocytosis rate of monocyte-derived macrophages (MDMs). To examine whether exogenous AAT is able to alleviate the inhibitory effect of α-defensins on macrophage function, we incubated MDMs with AAT prior to α-defensin treatment and demonstrate that AAT improves the migratory ability and phagocytic ability of MDMs compared with MDMs incubated only with α-defensins. Taken together, this study suggests that a high concentration of α-defensins inhibits the activation of ERK/STAT3 signaling, negatively regulates the expression of M2 macrophage markers, and impairs innate immune function of macrophages. [ABSTRACT FROM AUTHOR]

Between 2016 and 2018, Brazil faced a yellow fever (YF) outbreak, which led to an expansion of vaccination coverage. The coexistence of the YF outbreak and the HIV-1 epidemic in Brazil raised concerns regarding the immune response and vaccine effectiveness in individuals living with HIV (PLWH). The aim of this study was to investigate the immune response to YF vaccination in PLWH and HIV-uninfected individuals as controls. Transcript levels of immunomodulatory molecules, including IL-6, IL-10, IL-21, TGF-β, CD19, CD163, miR-21, miR-146, and miR-155, were measured using RT qPCR. TCD4+ cells were evaluated by cytometry, and neutralizing antibody (Nab) titers were detected by a micro plaque-reduction neutralization test. The findings of our study revealed several noteworthy observations. First, there was a notable reduction in the circulation of TCD4+ cells postvaccination. Among people living with HIV (PLWH), we observed an increase in the expression of IL-10 following vaccination, while IL-6 expression was diminished in PLWH with lower TCD4+ counts. Furthermore, we identified the downregulation of CD19 and TGF-β, along with the upregulation of IL-21 and CD163. Notably, we observed positive correlations between the levels of IL-10/IL-21, IL-10/CD163, and IL-6/CD19. Additionally, there was a positive correlation between miRNAs 146 and 155. It is important to emphasize that all participants exhibited robust neutralizing antibody responses after receiving 17DD YF vaccination. In this context, the gene expression data presented can be useful for biomarker studies of protective antibodies induced by YF vaccination. This study sheds light on immune mechanisms in individuals living with HIV and YF vaccination. • The yellow fever vaccine (YFV) induced a decrease in circulating CD4+ T cells. • Individuals living with HIV (PLWH) achieved levels of antibodies neutralizing against YF. • YFV induced different levels of IL-10 expression between PLWH and controls. • Correlations between cytokines showed crosstalk in the YF vaccine immune response. [ABSTRACT FROM AUTHOR]

Hemoglobin-based oxygen carriers (HBOCs) as blood substitutes are one of the great hopes of modern transfusion and emergency medicine. After the major safety-relevant challenges of the last decades seem to be largely overcome, current developments have in common that they are affected by degradation and excretion at an early stage in test organisms. Several possible mechanisms that may be responsible for this are discussed in the literature. One of them is CD163, the receptor of the complex of haptoglobin (Hp) and hemoglobin (Hb). The receptor has been shown in various studies to have a direct affinity for Hb in the absence of Hp. Thus, it seems reasonable that CD163 could possibly also bind Hb within HBOCs and cause phagocytosis of the particles. In this work we investigated the role of CD163 in the uptake of our hemoglobin sub-micron particles (HbMPs) in monocytes and additionally screened for alternative ways of particle recognition by monocytes. In our experiments, blockade of CD163 by specific monoclonal antibodies proved to partly inhibit HbMP uptake by monocytes. It appears, however, that several other phagocytosis pathways for HbMPs might exist, independent of CD163 and also Hb.

Background and Objectives: This study presents a retrospective analysis of 26 autopsy cases from a single centre, primarily focusing on forensic cases, with a majority of male individuals. Materials and Methods: We systematically analysed autopsy reports and cardiac tissue slides using haematoxylin-eosin stain and immunohistochemistry for CD3, CD163, and IL-6. The histological assessment evaluated key variables such as inflammation severity, necrosis, and background changes using a standardised grading system. Quantitative analysis of immunohistochemical markers was performed, calculating the percentage of positively stained cells within the inflammatory infiltrate. Results: The average age was 51.6 years, slightly skewed towards older males. The fatalities varied widely, with sudden death and drug abuse being the most common conditions linked to myocarditis findings on histological examination. A strong correlation was found between the severity of inflammation (measured by size within a myocardium section) and the scoring system based on the number of inflammatory foci per section (p ≤ 0.001). Most cases showed mild to minimal fibrosis, with some exhibiting moderate to severe fibrosis, arteriosclerosis, and myocyte hypertrophy. The presence of protein CD3 in the inflammatory infiltrate revealed a moderate inverse correlation between the CD3 values and the severity of inflammation and necrosis, and a strong inverse correlation with neutrophil levels. CD3 levels were higher in sudden death cases and lower in cases with numerous inflammatory foci, highlighting the discreet nature of lymphocytic myocarditis. Macrophage presence, assessed using CD163, showed a moderate inverse correlation with neutrophil levels and significant differences between sudden death and non-sudden death cases. Macrophage-rich inflammation was observed in cases with pneumonia/bronchopneumonia-associated lesions. IL-6 expression showed a moderate direct correlation with inflammation severity (p = 0.028), severity of necrosis (p = 0.005), and the number of inflammatory foci per section (p = 0.047). A moderate inverse correlation was found between CD3 and IL-6 expression (p = 0.005). Conclusions: These findings highlight the need for a unique immunohistochemical approach in forensic cases of myocarditis, differing from guidelines for endomyocardial biopsies due to diverse inflammatory cells. The study suggests exploring inflammatory chemokines within myocarditis foci for their significance in clinical scenarios. Specifically, IL-6, a crucial pro-inflammatory interleukin, correlated significantly with the severity of inflammation and necrosis (p < 0.05). This study provides novel and valuable insights into the histopathological and immunological markers of myocarditis in autopsy cases.