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Background: Lupus nephritis (LN) is a severe manifestation of systemic lupus erythematosus (SLE), characterized by inflammation and immune dysregulation in the kidneys. The role of macrophage polarization in LN progression remains underexplored. Objective: This study examined the association between tubulointerstitial M1/M2 macrophage subpopulations and LN indices of activity and chronicity. Materials and Methods: We retrospectively reviewed 160 renal biopsy specimens in patients with LN (ISN/RPS classes II–V) from the database of the Department of Anatomical Pathology, the Faculty of Medicine Vajira Hospital, Navamindradhiraj University (2012–2021). Additional immunohistochemical analysis included CD68, iNOS, CD206, CD163, and evaluation of infiltration with M1 (iNOS+), M2a (CD206+), and M2c macrophages (CD163+). Moreover, clinical information at the time of the renal biopsy, including age, sex, and laboratory findings, was obtained from the electronic medical records. The data were correlated with the macrophage infiltration using the Spearman test. Results: Lupus nephritis biopsies with ISN/RPS class II–V were included (class II: 3 cases (2%), III: 30 cases (19%), III + V: 16 cases (10%), IV: 73 cases (46%), IV + V: 18 cases (11%), and V: 20 cases (12%)). In addition, the mean age of SLE patients at the time of biopsy was 33 years (range: 19–47 years). Most patients were females (n = 141; 88%). The population of CD68+ macrophages was related to serum creatinine (p < 0.001; rs = 0.34). We detected predominantly M2 macrophages across all LN classes, but M1 macrophages demonstrated significant correlations with the activity index (p < 0.001; rs = 0.43). Conversely, M2a and M2c subpopulations were strongly associated with the chronicity index (M2a: p < 0.001, rs = 0.48; M2c: p = 0.024, rs = 0.18). Total macrophages correlated with both indices (activity: p < 0.001, rs = 0.44; chronicity: p < 0.001, rs = 0.42). Conclusions: In lupus nephritis, the predominant population of macrophages is M2. Correlations were noted between the subpopulations of M1 and M2c macrophages and the activity and chronicity indices, respectively. In addition, macrophage populations correlated with disease progression, but the significance of this association in disease progression remains uncertain. [ABSTRACT FROM AUTHOR]

Xiang Xu,1,2 Fuling Qiu,2 Man Yang,3 Xiaoyong Liu,2 Siming Tao,4,&ast; Bingrong Zheng1,&ast; 1School of Medicine, Yunnan University, Kunming City, Yunnan Province, People’s Republic of China; 2Department of Cardiology, The Second Affiliated Hospital of Kunming Medical University, Kunming City, Yunnan Province, People’s Republic of China; 3School of Medicine, Dali University, Dali City, Yunnan Province, People’s Republic of China; 4Department of Cardiology, The Affiliated Hospital of Yunnan University, Kunming City, Yunnan Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Bingrong Zheng; Siming Tao, Email zhengbr@ynu.edu.cn; taosm6450@ynu.edu.cnBackground: Dysregulated macrophages are important causes of Atherosclerosis (AS) formation and increased plaque instability, but the heterogeneity of these plaques and the role of macrophage subtypes in plaque instability have yet to be clarified.Methods: This study integrates single-cell and bulk-seq data to analyze atherosclerotic plaques. Unsupervised clustering was used to reveal distinct plaque subtypes, while survival analysis and gene set variation analysis (GSVA) methods helped in understanding their clinical outcomes. Enrichment of differential expression of macrophage genes (DEMGs) score and pseudo-trajectory analysis were utilized to explore the biological functions and differentiation stages of macrophage subtypes in AS progression. Additionally, CellChat and the BayesPrism deconvolution method were used to elucidate macrophage subtype interaction and their prognostic significance at single-cell resolution. Finally, the expression of biomarkers was validated in mouse experiments.Results: Three distinct AS plaque subtypes were identified, with cluster 3 plaque subtype being particularly associated with higher immune infiltration and poorer prognosis. The DEMGs score exhibited a significant elevation in three macrophage subtypes (SPP1+/VCAN+ macrophages, IL1B+ macrophages, and FLT3LG+ macrophages), associated with cluster 3 plaque subtype and highlighted the prognostic significance of these subtypes. Activation trajectory of the macrophage subtypes is divided into three states (Pre-branch, Cell fate 1, and Cell fate 2), and Cell fate 2 (SPP1+/VCAN+ macrophages, IL1B+ macrophages, and FLT3LG+ macrophages dominant) exhibiting the highest DEMGs score, distinct interactions with other cell components, and relating to poorer prognosis of ischemic events. This study also uncovered a unique SPP1+/VCAN+ macrophage subtype, rare in quantity but significant in influencing AS progression. Machine learning algorithms identified 10 biomarkers crucial for AS diagnosis. The validation of these biomarkers was performed using Mendelian Randomization analysis and in vitro methods, supporting their relevance in AS pathology.Conclusion: Our study provides a comprehensive view of AS plaque heterogeneity and the prognostic significance of macrophage subtypes in plaque instability. Keywords: atherosclerosis, macrophage subtypes, single-cell analysis, plaque heterogeneity, biomarkers, pseudo-trajectory analysis

Background: Dysregulated macrophages are important causes of Atherosclerosis (AS) formation and increased plaque instability, but the heterogeneity of these plaques and the role of macrophage subtypes in plaque instability have yet to be clarified. Methods: This study integrates single-cell and bulk-seq data to analyze atherosclerotic plaques. Unsupervised clustering was used to reveal distinct plaque subtypes, while survival analysis and gene set variation analysis (GSVA) methods helped in understanding their clinical outcomes. Enrichment of differential expression of macrophage genes (DEMGs) score and pseudo-trajectory analysis were utilized to explore the biological functions and differentiation stages of macrophage subtypes in AS progression. Additionally, CellChat and the BayesPrism deconvolution method were used to elucidate macrophage subtype interaction and their prognostic significance at single-cell resolution. Finally, the expression of biomarkers was validated in mouse experiments. Results: Three distinct AS plaque subtypes were identified, with cluster 3 plaque subtype being particularly associated with higher immune infiltration and poorer prognosis. The DEMGs score exhibited a significant elevation in three macrophage subtypes (SPP1+/VCAN+ macrophages, IL1B+ macrophages, and FLT3LG+ macrophages), associated with cluster 3 plaque subtype and highlighted the prognostic significance of these subtypes. Activation trajectory of the macrophage subtypes is divided into three states (Pre-branch, Cell fate 1, and Cell fate 2), and Cell fate 2 (SPP1+/VCAN+ macrophages, IL1B+ macrophages, and FLT3LG+ macrophages dominant) exhibiting the highest DEMGs score, distinct interactions with other cell components, and relating to poorer prognosis of ischemic events. This study also uncovered a unique SPP1+/VCAN+ macrophage subtype, rare in quantity but significant in influencing AS progression. Machine learning algorithms identified 10 biomarkers crucial for AS diagnosis. The validation of these biomarkers was performed using Mendelian Randomization analysis and in vitro methods, supporting their relevance in AS pathology. Conclusion: Our study provides a comprehensive view of AS plaque heterogeneity and the prognostic significance of macrophage subtypes in plaque instability. [ABSTRACT FROM AUTHOR]

Introduction: Symptomatic juvenile idiopathic arthritis (sJIA) is an autoinflammatory disease, and monocytes/macrophages play an important role. However, which macrophage subtype plays a major role in different stages of sJIA is still unclear. This study aimed to explore macrophage subtypes in different stages of sJIA. Methods: Twenty-two children with sJIA who were followed up at Shanghai Children's Hospital from January 2018 to December 2020 were enrolled in this study. sJIA children were divided into an activity group (n = 12) and an inactivity group (n = 10). In the activity group, subjects with newly diagnosed sJIA and untreated were included; in the inactivity group, subjects with inactive sJIA meeting the 2011 ACR criteria for sJIA were recruited. Ten children with orthostatic proteinuria served as controls. Peripheral blood was collected. Flow cytometry was performed to detect macrophage subtypes: M1 (CD14+CD86+CD80+), M2a (CD14+CD206+CD301+), M2b (CD14+CD206+CD86+) and M2c (CD14+CD206+CD163+), and the contents of cytokines were also examined, including interleukins (IL) (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10 and IL-17), interferon-α, interferon-γ, and tumor necrosis-α. Results: M1 marker CD80 and M2 marker CD163, CD301 were highly expressed in children with active sJIA. The majority of macrophages were M1 and M2a in the activity group (P < 0.05). In the inactivity group, M2 tended to polarize into M2b and M2c (P < 0.05). IL-6 significantly increased in the activity group (P < 0.05), while IL-10, IL-4 and IL-17 markedly increased in the inactivity group (P < 0.05). Conclusions: In the active sJIA, M1 activation promotes inflammation, while M2a rapidly responds to inhibit inflammation; in the inactive sJIA, M2b and M2c play a major role in inhibiting inflammation. [ABSTRACT FROM AUTHOR]

Background: Macrophages control innate and acquired immunity, but their role in severe asthma remains ill‐defined. We investigated gene signatures of macrophage subtypes in the sputum of 104 asthmatics and 16 healthy volunteers from the U‐BIOPRED cohort. Methods: Forty‐nine gene signatures (modules) for differentially stimulated macrophages, one to assess lung tissue‐resident cells (TR‐Mφ) and two for their polarization (classically and alternatively activated macrophages: M1 and M2, respectively) were studied using gene set variation analysis. We calculated enrichment scores (ES) across severity and previously identified asthma transcriptome‐associated clusters (TACs). Results: Macrophage numbers were significantly decreased in severe asthma compared to mild‐moderate asthma and healthy volunteers. The ES for most modules were also significantly reduced in severe asthma except for 3 associated with inflammatory responses driven by TNF and Toll‐like receptors via NF‐κB, eicosanoid biosynthesis via the lipoxygenase pathway and IL‐2 biosynthesis (all P <.01). Sputum macrophage number and the ES for most macrophage signatures were higher in the TAC3 group compared to TAC1 and TAC2 asthmatics. However, a high enrichment was found in TAC1 for 3 modules showing inflammatory pathways linked to Toll‐like and TNF receptor activation and arachidonic acid metabolism (P <.001) and in TAC2 for the inflammasome and interferon signalling pathways (P <.001). Data were validated in the ADEPT cohort. Module analysis provides additional information compared to conventional M1 and M2 classification. TR‐Mφ were enriched in TAC3 and associated with mitochondrial function. Conclusions: Macrophage activation is attenuated in severe granulocytic asthma highlighting defective innate immunity except for specific subsets characterized by distinct inflammatory pathways. [ABSTRACT FROM AUTHOR]

Endometriosis is a chronic inflammatory disease associated with an impaired immune response at the site of lesion implantation. The ability of macrophages to respond to changes in their environment is critical for an effective immune response. However, the existing knowledge of the peritoneal immune cell populations, their activation state and contribution to the immunological changes that occur in endometriosis are still controversial and inconclusive. In this study, we have examined the relative abundance of peritoneal macrophage subtypes, in women with (n = 21) versus without (n = 18) endometriosis and disease-associated changes in the adaptive T cell response. Using flow cytometry, we showed that peritoneal fluid monocyte/macrophages are composed of two populations of cells that exhibit major differences in the levels of the CD14 and CD68 markers, which we classified as the CD14+low/CD68+low and CD14+high/CD68+high subpopulations. Moreover, endometriosis-associated changes in the macrophage subtypes occurred only in the CD14+low/CD68+low subpopulation. In this subpopulation, we found an increased macrophage type 2 response that was coupled with an increase in peritoneal T-helper 2 and T-regulatory cell populations in women with endometriosis, compared with controls. In summary, this study resolves conflicting data in the literature regarding changes in the peritoneal immune cell population in endometriosis and identifies CD14+low/CD68+low macrophages as the subpopulation that changes in response to the disease. [ABSTRACT FROM AUTHOR]

Background: Dysregulated macrophages are important causes of Atherosclerosis (AS) formation and increased plaque instability, but the heterogeneity of these plaques and the role of macrophage subtypes in plaque instability have yet to be clarified., Methods: This study integrates single-cell and bulk-seq data to analyze atherosclerotic plaques. Unsupervised clustering was used to reveal distinct plaque subtypes, while survival analysis and gene set variation analysis (GSVA) methods helped in understanding their clinical outcomes. Enrichment of differential expression of macrophage genes (DEMGs) score and pseudo-trajectory analysis were utilized to explore the biological functions and differentiation stages of macrophage subtypes in AS progression. Additionally, CellChat and the BayesPrism deconvolution method were used to elucidate macrophage subtype interaction and their prognostic significance at single-cell resolution. Finally, the expression of biomarkers was validated in mouse experiments., Results: Three distinct AS plaque subtypes were identified, with cluster 3 plaque subtype being particularly associated with higher immune infiltration and poorer prognosis. The DEMGs score exhibited a significant elevation in three macrophage subtypes (SPP1 + /VCAN + macrophages, IL1B + macrophages, and FLT3LG + macrophages), associated with cluster 3 plaque subtype and highlighted the prognostic significance of these subtypes. Activation trajectory of the macrophage subtypes is divided into three states (Pre-branch, Cell fate 1, and Cell fate 2), and Cell fate 2 (SPP1 + /VCAN + macrophages, IL1B + macrophages, and FLT3LG + macrophages dominant) exhibiting the highest DEMGs score, distinct interactions with other cell components, and relating to poorer prognosis of ischemic events. This study also uncovered a unique SPP1 + /VCAN + macrophage subtype, rare in quantity but significant in influencing AS progression. Machine learning algorithms identified 10 biomarkers crucial for AS diagnosis. The validation of these biomarkers was performed using Mendelian Randomization analysis and in vitro methods, supporting their relevance in AS pathology., Conclusion: Our study provides a comprehensive view of AS plaque heterogeneity and the prognostic significance of macrophage subtypes in plaque instability., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Xu et al.)

Innate inflammation is a hallmark of both experimental and human atherosclerosis. The predominant innate immune cell in the atherosclerotic plaque is the monocyte-macrophage. The behaviour of this cell type within the plaque is heterogeneous and depends on the recruitment of diverse monocyte subsets. Furthermore, the plaque microenvironment offers polarisation and activation signals which impact on phenotype. Microenvironmental signals are sensed through pattern recognition receptors, including toll-like and NOD-like receptors - the latter of which are components of the inflammasome - thus dictating macrophage behaviour and outcome in atherosclerosis. Recently cholesterol crystals and modified lipoproteins have been recognised as able to directly engage these pattern recognition receptors. The convergent role of such pathways in terms of macrophage activation is discussed in this review. [ABSTRACT FROM AUTHOR]

Abstract Innate inflammation is a hallmark of both experimental and human atherosclerosis. The predominant innate immune cell in the atherosclerotic plaque is the monocyte-macrophage. The behaviour of this cell type within the plaque is heterogeneous and depends on the recruitment of diverse monocyte subsets. Furthermore, the plaque microenvironment offers polarisation and activation signals which impact on phenotype. Microenvironmental signals are sensed through pattern recognition receptors, including toll-like and NOD-like receptors - the latter of which are components of the inflammasome - thus dictating macrophage behaviour and outcome in atherosclerosis. Recently cholesterol crystals and modified lipoproteins have been recognised as able to directly engage these pattern recognition receptors. The convergent role of such pathways in terms of macrophage activation is discussed in this review.

Macrophages play a complex role in tumor progression since they can exert both tumor-preventing (M1 macrophages) and tumor-promoting (M2 macrophages) activities. In colorectal carcinoma (CRC), at odds to many other cancers, macrophage infiltration has been correlated with an improved patient survival. In a recent study, we have evaluated the distribution of M1 and M2 macrophage subtypes in CRC and their impact on patient prognosis. [ABSTRACT FROM AUTHOR]

Background: The role of macrophages in the pathogenesis of lupus nephritis, in particular their differentiation to a certain subtype (e.g., M1- or M2-like) modulating the inflammatory reaction, is unknown. Here we investigated whether the differentiation in M1- or M2-like macrophages depends on the stage of lupus nephritis and whether this correlates with clinical parameters., Method: Using immunohistochemical analysis we analyzed renal biopsies from 68 patients with lupus nephritis (ISN/RPS classes II-V) for infiltration with M1-like (iNOS+/CD68+), M2a-like (CD206+/CD68+), M2c-like macrophages (CD163+/CD68+), and FoxP3+ regulatory T-cells. In addition, clinical parameters at the time of renal biopsy, i.e., blood pressure, proteinuria and serum urea were correlated with the macrophage infiltration using the Spearman test., Results: The mean number of CD68+ macrophages was related to the diagnosed ISN/RPS class, showing the highest macrophage infiltration in biopsies with diffuse class IV and the lowest number in ISN/RPS class V. In all ISN/RPS classes we detected more M2c-like CD163+/CD68+ than M2a-like CD206+/CD68+ cells, while M1-macrophages played only a minor role. Cluster analysis using macrophage subtype numbers in different renal compartments revealed three main clusters showing cluster 1 dominated by class V. Clusters 2 and 3 were dominated by lupus class IV indicating that this class can be further differentiated by its macrophage population. The number of tubulointerstitial FoxP3+ cells correlated with all investigated macrophage subtypes showing the strongest association to numbers of M2a-like macrophages. Kidney function, as assessed by serum creatinine and serum urea, correlated positively with the number of total CD68+, M2a-like and M2c-like macrophages in the tubulointerstitium. In addition, total CD68+ and M2c-like macrophage numbers highly correlated with Austin activity score. Interestingly, in hypertensive lupus patients only the number of M2a-like macrophages was significantly increased compared to biopsies from normotensive lupus patients., Conclusion: M2-like macrophages are the dominant subpopulation in human lupus nephritis and particularly, M2a subpopulations were associated with disease progression, but their role in disease progression remains unclear.