Search

CCR4 is a chemokine receptor highly expressed by Th2 cells, and regarded as a potential therapeutic target for atopic dermatitis (AD). CCL17 and CCL22 are the CCR4 ligands, and thymic stromal lymphopoietin (TSLP) is shown to promote the expression of CCL17 and CCL22 by dendritic cells. Here, by using dibutyl phthalate (DBP), a TSLP inducer, and a hydrogel patch as a transcutaneous delivery device for ovalbumin, we developed a novel murine AD model and investigated the effect of Compound 22, a CCR4 antagonist. We first found that the mRNA expression of TSLP together with CCL17 and CCL22 was increased in the skins treated with DBP. Furthermore, the topical application of ovalbumin and DBP efficiently and rapidly induced AD-like skin lesions in BALB/c mice, which were characterized by ear swelling accompanied by infiltration of eosinophils, mast cells, and CCR4-expressing Th2 cells in the skin lesions, and elevated total IgE levels in the sera. Using this AD model, we demonstrated that cutaneous administration of Compound 22 inhibited Th2 cell infiltration and ameliorated the AD-like skin lesions. These results suggest that our AD model could be useful for studying new therapeutic strategies. Collectively, CCR4 antagonists may be a promising approach for treating AD.

Macrophages are dynamic cells susceptible to the local microenvironment which includes tumor-associated macrophages (TAMs) in cancers. TAMs are a collection of heterogeneous macrophages, including M1 and M2 subtypes, shaped by various activation modes and labeled with various markers in different tumors. CCL22+-infiltrating cells are thought to be significantly associated with the prognosis of cervical cancer patients. Moreover, CCL22 is an established marker of M2a macrophages. Although the phenotypic identification of M1 and M2 macrophages is well established in mice and human macrophages cultured in a medium with fetal calf serum (FCS), fewer studies have focused on M2 subtypes. In addition, the question of whether CCL22 affects polarization of M2a macrophages remains unanswered. This study constructed a co-culture system to shape TAMs in vitro. We found that CCL22 was mainly secreted by TAMs but not cervical cancer cell lines. Human peripheral blood monocytes were differentiated into uncommitted macrophages (M0) and then polarized to M1, M2a, M2b, and M2c macrophages using LPS plus IFNr, IL-4, LPS plus IL1β, and IL-10, respectively. Using flowcytometry, we found CD80++ was the marker of M1 and M2b, CD206++ was the marker of M2a, and CD163++ was the marker of M2c, compared with M0 macrophages. By regulating CCL22, we found that the mean fluorescence intensity (MFI) of CD206 in TAMs was significantly affected compared to the control group. Therefore, CCL22 could polarize TAMs of cervical cancer toward M2a macrophages. In conclusion, our study revealed that CCL22 could be a therapeutic target for cervical cancer, which might be because of its role in regulating macrophage polarization.

Atypical chemokine receptors (ACKRs) have emerged as important regulators or scavengers of homeostatic and inflammatory chemokines. Among these atypical receptors, ACKR4 is reported to bind the homeostatic chemokines CCL19, CCL21, CCL25 and CXCL13. In a recent study by Matti et al., the authors show that ACKR4 is also a receptor for CCL20, previously established to bind to CCR6 only. They provide convincing evidence that, just as for its other chemokine ligands, ACKR4 rapidly internalizes CCL20 both in vitro and in vivo. Independently of this discovery, we undertook a screening program aiming at reassessing the activity of the 43 human chemokines toward ACKR4 using a highly sensitive β‐arrestin recruitment assay. This systematic analysis confirmed CCL20 as a new agonist ligand for ACKR4 in addition to CCL19, CCL21, and CCL25. Furthermore, CCL22, which plays an important role in both homeostasis and inflammatory responses, and is known as a ligand for CCR4 and ACKR2 was found to also act as a potent partial agonist of ACKR4. In contrast, agonist activity of CXCL13 toward ACKR4 was disproved. This independent wide‐range systematic study confirms the pairing of CCL20 with ACKR4 newly discovered by Matti and co‐authors, and further refines the spectrum of chemokines activating ACKR4. [ABSTRACT FROM AUTHOR]

Neuropathic pain is a chronic condition that remains a major clinical problem owing to high resistance to available therapy. Recent studies have indicated that chemokine signaling pathways are crucial in the development of painful neuropathy; however, the involvement of CC chemokine receptor 4 (CCR4) has not been fully elucidated thus far. Therefore, the aim of our research was to investigate the role of CCR4 in the development of tactile and thermal hypersensitivity, the effectiveness of morphine/buprenorphine, and opioid-induced tolerance in mice exposed to chronic constriction injury (CCI) of the sciatic nerve. The results of our research demonstrated that a single intrathecal or intraperitoneal administration of C021, a CCR4 antagonist, dose dependently diminished neuropathic pain-related behaviors in CCI-exposed mice. After sciatic nerve injury, the spinal expression of CCL17 and CCL22 remained unchanged in contrast to that of CCL2, which was significantly upregulated until day 14 after CCI. Importantly, our results provide evidence that in naive mice, CCL2 may evoke pain-related behaviors through CCR4 because its pronociceptive effects are diminished by C021. In CCI-exposed mice, the pharmacological blockade of CCR4 enhanced the analgesic properties of morphine/buprenorphine and delayed the development of morphine-induced tolerance, which was associated with the silencing of IBA-1 activation in cells and decrease in CCL2 production. The obtained data suggest that the pharmacological blockade of CCR4 may be a new potential therapeutic target for neuropathic pain polytherapy.

Mogamulizumab is a humanized anti‐C‐C chemokine receptor type (CCR)4 antibody that shows cytotoxicity against CCR4+ lymphoma cells via antibody‐dependent cell‐mediated cytotoxicity in advanced cutaneous T cell lymphoma (CTCL) patients. The production levels of ligands for CCR4, that is, Chemokine (C‐C motif) ligand (CCL)17 and CCL22, are important for the assessment of the disease activity in CTCL patients. We evaluated the serum levels of CCL17, CCL19, CCL22, C‐X‐C motif chemokine ligand (CXCL)10, and CXCL13, which are ligands for CCR4, CCR7, CCR4, C‐X‐C Motif Chemokine Receptor (CXCR)3, and CXCR5, respectively, at baseline and 4 weeks after the administration of mogamulizumab in five patients with mycosis fungoides. The serum levels of CCL22 were significantly decreased in patients who responded to mogamulizumab, but no differences were identified in the serum levels of CCL17, CCL19, CXCL10, or CXCL13. Immunofluorescence staining revealed that the majority of CCL22‐producing cells were cluster of differentiation (CD)163+ tumor‐associated macrophages, and they were surrounded by CCR4+ CTCL cells. Our present data suggested that the serum CCL22 level may be a predictive marker of the efficacy of mogamulizumab for the treatment of CCR4+ CTCL. [ABSTRACT FROM AUTHOR]

• In a mouse model of diabetic neuropathic pain, mRNA and protein level of CCL2 is spinally upregulated on day 7. • Single administration (i.p./ i.t.) of CCR4 antagonist (C021), but not CCR2 (RS504393), attenuates pain-related behavior. • CCR4 antagonist (C021) beneficially affects balance and motor coordination of animals. • CCR4 antagonist (C021) enhances morphine and buprenorphine analgesia. Chemokine signaling has been implicated in the pathogenesis of diabetic neuropathy; however, the role of chemokine CC motif receptor 4 (CCR4) remains unknown. The goal was to examine the function of CCR4 in hypersensitivity development and opioid effectiveness in diabetic neuropathy. Streptozotocin (STZ; 200 mg/kg, intraperitoneally administered)-induced mouse model of diabetic neuropathy were used. An analysis of the mRNA/protein expression of CCR4 and its ligands was performed by qRT-PCR, microarray and/or Western blot methods. C021 (CCR4 antagonist), morphine and buprenorphine were injected intrathecally or intraperitoneally, and pain-related behavior was evaluated by the von Frey, cold plate and rotarod tests. We observed that on day 7 after STZ administration, the blood glucose level was increased, and as a consequence, hypersensitivity to tactile and thermal stimuli developed. In addition, we observed an increase in the mRNA level of CCL2 but not CCL17/CCL22. The microarray technique showed that the CCL2 protein level was also upregulated. In naive mice, the pronociceptive effect of intrathecally injected CCL2 was blocked by C021, suggesting that this chemokine acts through CCR4. Importantly, our results provide the first evidence that in a mouse model of diabetic neuropathy, single intrathecal and intraperitoneal injections of C021 diminished neuropathic pain-related behavior in a dose-dependent manner and improved motor functions. Moreover, both single intrathecal and intraperitoneal injections of C021 enhanced morphine and buprenorphine effectiveness. These results reveal that pharmacological modulation of CCR4 may be a good potential therapeutic target for the treatment of diabetic neuropathy and may enhance the effectiveness of opioids. [ABSTRACT FROM AUTHOR]

Neuropathic pain is a chronic condition that remains a major clinical problem owing to high resistance to available therapy. Recent studies have indicated that chemokine signaling pathways are crucial in the development of painful neuropathy; however, the involvement of CC chemokine receptor 4 (CCR4) has not been fully elucidated thus far. Therefore, the aim of our research was to investigate the role of CCR4 in the development of tactile and thermal hypersensitivity, the effectiveness of morphine/buprenorphine, and opioid-induced tolerance in mice exposed to chronic constriction injury (CCI) of the sciatic nerve. The results of our research demonstrated that a single intrathecal or intraperitoneal administration of C021, a CCR4 antagonist, dose dependently diminished neuropathic pain-related behaviors in CCI-exposed mice. After sciatic nerve injury, the spinal expression of CCL17 and CCL22 remained unchanged in contrast to that of CCL2 , which was significantly upregulated until day 14 after CCI. Importantly, our results provide evidence that in naive mice, CCL2 may evoke pain-related behaviors through CCR4 because its pronociceptive effects are diminished by C021. In CCI-exposed mice, the pharmacological blockade of CCR4 enhanced the analgesic properties of morphine/buprenorphine and delayed the development of morphine-induced tolerance, which was associated with the silencing of IBA-1 activation in cells and decrease in CCL2 production. The obtained data suggest that the pharmacological blockade of CCR4 may be a new potential therapeutic target for neuropathic pain polytherapy. [ABSTRACT FROM AUTHOR]

Fetal liver (FL) is the major embryonic hematopoietic organ and a site where circulating hematopoietic stem/progenitor cells (HSPCs) reside. However, HSPC migration/retention mechanisms in FL remain unclear. A chemokine screen revealed that the CCR4 ligands CCL17 and CCL22 are highly expressed in mouse embryonic day (E) 12.5 FL. Flow cytometric analysis confirmed CCR4 expression in FL HSPCs. To identify sources of CCL17 and CCL22, we fractionated FL into various cell types and found that Ccl17 and Ccl22 were predominantly expressed in HPCs/matured HCs. In vitro cell migration analysis confirmed enhanced HSPC migration in the presence of HPCs/matured HCs. Furthermore, exo-utero injection of anti-CCR4 neutralizing antibody into pregnant mice significantly reduced the number of FL HSPCs in embryos. These data demonstrate a paracrine mechanism by which HSPC migration/retention is regulated by CCL17 and CCL22 secreted from HPCs or matured HCs in FL. • CC chemokines are highly expressed in FL and FL HSPCs express cognate CCR4 receptors. • The presence of FL HCs expressing CCL17 and CCL22 promotes HSPC migration in vitro. • In vivo inhibition of CCR4 signaling decreases the number of HSPCs in FL. • Paracrine CCL17 and CCL22 signaling regulates HSPC migration or retention in FL. [ABSTRACT FROM AUTHOR]

Abnormality in the number and function of CD4+CD25+FOXP3+ regulatory T cells (Tregs) in peripheral blood has been linked to the initiation and progression of rheumatoid arthritis (RA). Effect of chemokine CCL22 on the number of Tregs in CD4+ T cells and the underlying mechanism were investigated. Downregulation of peripheral Tregs were observed while upregulation of serum chemokine CCL22 in RA patients. Tregs count and the expression of FOXP3 (Tregs function-related maker) and phosphorylated-signal transducer and activator of transcription 5 (p-STAT5) in CD4+ T cells from RA patients were increased while C-C chemokine receptor 4 (CCR4) was decreased by anti-CCL22 antibody, however, recombinant CCL22 resulted in the opposite effects in CD4+ T cells from the healthy control. STAT5 inhibitor significantly reversed the effects of anti-CCL22 antibody. Similarly, sinomenine, an anti-arthritis drug, which decreased CCL22 and CCR4, showed the same trends as the above events, and was reversed by recombinant CCL22 or STAT5 inhibitor. Collectively, anti-CCL22 induced the number of Tregs via STAT5 pathway, leading to expansion of Tregs and subsequently to control of the autoimmune reaction in RA patients. Our study provides s novel strategy for RA treatment. [ABSTRACT FROM AUTHOR]

Background: CCL22 played critical roles in Tregs recruitment. The upstream regulators modulating CCL22 in hepatocellular carcinoma (HCC) were not clearly understood. Methods: MiR‐23a, p‐p65, p65, CCL22, and Foxp3 levels were monitored by RT‐qPCR and western blotting. Immunofluorescence assay was used to perform the costaining of Foxp3 and CD4 on liver tissues. Transwell assay was applied to evaluate the migration ability of Tregs. Dual‐luciferase assay was performed to determine relationship of miR‐23a/CCL22 and p65/miR‐23a. Chromatin immunoprecipitation (ChIP) was applied to detect the direct binding of p65 to miR‐23a promoter. Xenograft tumor models were developed to investigate the functions of p65 and miR‐23a in vivo. Results: HBV infection was associated with reduced survival and increased Tregs recruitment in HCC patients. MiR‐23a was decreased, whereas p65, CCL22, and Foxp3 were increased in HBV+ tumors. MiR‐23a was inversely correlated with CCL22 and Foxp3 expression in HCC. MiR‐23a directly targeted CCL22 3'UTR, leading to CCL22 reduction and attenuated Tregs recruitment. Meanwhile, p65 functioned as a transcription repressor of miR‐23a by directly binding to its promoter. Inhibition of p65 induced miR‐23 expression, leading to less CCL22 expression and Tregs recruitment in vitro. CCL22 was the indispensable effector underlying p65/miR‐23a axis and Tregs recruitment. MiR‐23a inhibitor promoted xenografted tumor growth accompanying with upregulation of CCL22, whereas p65 inhibition exerted opposite effects. Conclusion: Blockage of p65 disinhibited miR‐23a expression, leading to CCL22 reduction and repress Tregs recruitment. Targeting p65/miR‐23a/CCL22 axis was a novel approach for HBV+ HCC treatment. [ABSTRACT FROM AUTHOR]

Bexarotene is a third-generation retinoid X receptor-selective retinoid that has been approved for use in the treatment of both early and advanced cutaneous T-cell lymphoma (CTCL). Although bexarotene has been used for decades in the treatment of CTCL, little is known about the mechanisms underlying its anti-tumor effects in CTCL patients. This study therefore focused on the immunomodulatory effects of bexarotene in vivo using an EL4 mouse T-cell lymphoma model, followed by investigation in CTCL patients treated with bexarotene. Intraperitoneal injection of bexarotene significantly decreased expressions of CCL22, CXCL5, CXCL10, and p19 in the tumor microenvironment. Based on those results, we then evaluated serum levels of CCL22, CXCL5, and CXCL10 in 25 patients with CTCL, revealing that CCL22 was significantly increased in advanced CTCL compared with early CTCL. Next, we evaluated serum levels of CCL22, CXCL5, and CXCL10 in CTCL patients treated with bexarotene. Serum levels of CCL22 were significantly decreased in 80% of CTCL patients who responded to bexarotene therapy. In addition, immunofluorescence staining revealed CD163+ M2 macrophages as the main source of CCL22. Moreover, bexarotene decreased the production of CCL22 by M2 macrophages generated from monocytes in vitro. Our findings suggest that the clinical benefits of bexarotene are partially attributable to suppressive effects on the production of CCL22 by M2-polarized tumor-associated macrophages.

Cytokine dynamics in patients with coronavirus disease 2019 (COVID-19) have been studied in blood but seldomly in respiratory specimens. We studied different cell markers and cytokines in fresh nasopharyngeal swab specimens for the diagnosis and for stratifying the severity of COVID-19. This was a retrospective case-control study comparing Myeloperoxidase (MPO), Adenosine deaminase (ADA), C-C motif chemokine ligand 22 (CCL22), Tumour necrosis factor alpha (TNFα) and Interleukin-6 (IL-6) mRNA expression in 490 (327 patients and 163 control) nasopharyngeal specimens from 317 (154 COVID-19 and 163 control) hospitalized patients. Of the 154 COVID-19 cases, 46 died. Both total and normalized MPO, ADA, CCL22, TNFα, and IL-6 mRNA expression levels were significantly higher in the nasopharyngeal specimens of infected patients when compared with controls, with ADA showing better performance (OR 5.703, 95% CI 3.424-9.500, p  < 0.001). Receiver operating characteristics (ROC) curve showed that the cut-off value of normalized ADA mRNA level at 2.37 × 10 -3 had a sensitivity of 81.8% and specificity of 83.4%. While patients with severe COVID-19 had more respiratory symptoms, and elevated lactate dehydrogenase, multivariate analysis showed that severe COVID-19 patients had lower CCL22 mRNA (OR 0.211, 95% CI 0.060-0.746, p  = 0.016) in nasopharyngeal specimens, while lymphocyte count, C-reactive protein, and viral load in nasopharyngeal specimens did not correlate with disease severity. In summary, ADA appears to be a better biomarker to differentiate between infected and uninfected patients, while CCL22 has the potential in stratifying the severity of COVID-19.

Oral cancer, a subtype of head and neck cancer, is characterized by increased infiltrating regulatory T cells (Treg); however, the pathological significance of the increase in Tregs in disease prognosis and progression and their underlying mechanism remain unestablished. C‐C motif chemokine ligand 22 (CCL22) has been implicated in the recruitment of Tregs. We used RT‐qPCR to determine CCL22 mRNA expression in clinical specimens and cultured cells. Loss‐of‐function and gain‐of‐function studies were carried out to analyze the effects of CCL22 modulations on cell proliferation, migration, invasion, and tumorigenesis and the mechanism involved in the deregulation of CCL22. In oral cancer specimens, CCL22 mRNA was upregulated. The increase was not only associated with reduced disease‐free survival but also strongly correlated with an increase in FOXP3 mRNA, a master regulator of Treg development and functions. Silencing CCL22 expression reduced cell proliferation, migration, and invasion, whereas ectopic overexpression showed opposite effects. Manipulation of CCL22 expression in cancer cells altered tumorigenesis in both immune‐compromised and ‐competent mice, supporting both autonomous and non‐autonomous actions of CCL22. Release of interleukin 1β (IL‐1β) from cancer‐associated fibroblasts (CAF) induces CCL22 mRNA expression in oral cancer cells by activating transcription factor nuclear factor kappa B (NF‐κB). Our data support a model in which CAF‐derived IL‐1β, CCL22, and its receptor CCR4 foster a protumor environment by promoting cell transformation and Treg infiltration. Intervention of the IL‐1β‐CCL22‐CCR4 signaling axis may offer a novel therapeutic strategy for oral cancer treatment. [ABSTRACT FROM AUTHOR]

Immune dysfunction often occurs in malignant pleural effusion (MPE). In our previous study, TGF-β derived predominantly from macrophages plays an important role in impairing T cell cytotoxicity in MPE. Therefore, we aimed to investigate whether other immunoregulatory cells and factors mediated TGF-β secretion from macrophages, involved in the immunosuppressive microenvironment of MPE, and to provide clues for potential immune therapy for MPE as well. We found that CCL22 level in MPE was significantly higher than that in non-malignant pleural effusion. The high level of CCL22 was closely associated with poor survival in MPE patients with lung cancer. CCL22 was dominantly produced by tumor-associated macrophages (TAMs) in MPE. Meanwhile, TAM-derived TGF-β mediated CCL22 expression in TAMs via c-Fos. CCL22 promoted the recruitment of regulatory T cells (Tregs) in MPE. Lastly, Treg-secreted high level of IL-8 further induced TGF-β production from TAMs, and promoted the immunosuppressive tumor microenvironment in MPE. Our results indicate that macrophage-derived CCL22 plays an important role in the immunosuppressive tumor microenvironment via IL-8 in MPE. [ABSTRACT FROM AUTHOR]

Vestibular Migraine (VM) and Meniere's Disease (MD) are episodic vestibular syndromes defined by a set of associated symptoms such as tinnitus, hearing loss or migraine features during the attacks. Both conditions may show symptom overlap and there is no biological marker to distinguish them. Two subgroups of MD patients have been reported, according to their IL-1β profile. Therefore, considering the clinical similarity between VM and MD, we aimed to investigate the cytokine profile of MD and VM as a means to distinguish these patients. We have also carried out gene expression microarrays and measured the levels of 14 cytokines and 11 chemokines in 129 MD patients, 82 VM patients, and 66 healthy controls. Gene expression profile in peripheral blood mononuclear cells (PBMC) showed significant differences in MD patients with high and low basal levels of IL- 1β and VM patients. MD patients with high basal levels of IL- 1β (MDH) had overall higher levels of cytokines/chemokines when compared to the other subsets. CCL4 levels were significantly different between MDH, MD with low basal levels of IL- 1β (MDL), VM and controls. Logistic regression identified IL- 1β, CCL3, CCL22, and CXCL1 levels as capable of differentiating VM patients from MD patients (area under the curve = 0.995), suggesting a high diagnostic value in patients with symptoms overlap. [ABSTRACT FROM AUTHOR]

Abstract Background Osteoarthritis (OA) is one of the leading causes of disability worldwide. Previous history of knee injury is a significant risk factor for OA. It has been established that low-level chronic inflammation plays a pivotal role in the onset and pathogenesis of OA. The primary aim of this research was to determine if a history of knee joint injury is associated with systemic inflammation. A secondary aim was to determine if systemic inflammation is related to knee pain and joint structure. Methods Differences in serum cytokine association networks, knee joint structural changes (MRI), and self-reported pain (i.e., Knee Injury and Osteoarthritis Outcome Score Pain subscale, KOOS PAIN and Intermittent and Constant Osteoarthritis Pain score, ICOAP) between individuals who had sustained a youth (aged 15–26 years) sport-related knee injury 3–10 years previously and age- and sex-matched controls were examined. Proteins of interest were also examined in an OA rat model. Results Cytokine association networks were found to differ significantly between study groups, yet no significant associations were found between networks and KOOS PAIN or MRI-defined OA. A group of cytokines (MCP1/CCL2, CCL22 and TNFα) were differentially associated with other cytokines between study groups. In a pre-clinical rat OA model, serum CCL22 levels were associated with pain (r = 0.255, p = 0.045) and structural changes to the cartilage. CCL22 expression was also observed in human OA cartilage and furthermore, CCL22 induced apoptosis of isolated human chondrocytes. Discussion These results suggest that CCL22 may be an early factor in the onset/pathogenic process of cartilage degeneration and/or related to pain OA. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Topical application of OVA and DBP increased TSLP, CCL17, and CCL22 expression. • Topical application of OVA and DBP enhanced Th2 cell infiltration in the skin. • Topical application of OVA and DBP induced acute AD-like skin lesions. • Cutaneous administration of a CCR4 antagonist ameliorated AD-like skin lesions. Abstract CCR4 is a chemokine receptor highly expressed by Th2 cells, and regarded as a potential therapeutic target for atopic dermatitis (AD). CCL17 and CCL22 are the CCR4 ligands, and thymic stromal lymphopoietin (TSLP) is shown to promote the expression of CCL17 and CCL22 by dendritic cells. Here, by using dibutyl phthalate (DBP), a TSLP inducer, and a hydrogel patch as a transcutaneous delivery device for ovalbumin, we developed a novel murine AD model and investigated the effect of Compound 22, a CCR4 antagonist. We first found that the mRNA expression of TSLP together with CCL17 and CCL22 was increased in the skins treated with DBP. Furthermore, the topical application of ovalbumin and DBP efficiently and rapidly induced AD-like skin lesions in BALB/c mice, which were characterized by ear swelling accompanied by infiltration of eosinophils, mast cells, and CCR4-expressing Th2 cells in the skin lesions, and elevated total IgE levels in the sera. Using this AD model, we demonstrated that cutaneous administration of Compound 22 inhibited Th2 cell infiltration and ameliorated the AD-like skin lesions. These results suggest that our AD model could be useful for studying new therapeutic strategies. Collectively, CCR4 antagonists may be a promising approach for treating AD. [ABSTRACT FROM AUTHOR]

Chronic pain is a major public health problem with limited effective therapeutic options. G-protein-coupled receptors play a significant role in pain modulation; however, whether and how G-protein-coupled receptor 183 participates in pain regulation remain unclear. In the present study, we found that G-protein-coupled receptor 183 expression was specifically upregulated in the hind paws of mice in various inflammatory pain models. Activation of G-protein-coupled receptor 183 induced acute pain, whereas inhibition or silencing of this receptor alleviated mechanical allodynia and thermal hyperalgesia in complete Freund's adjuvant (CFA) model. Mechanistically, activating G-protein-coupled receptor 183 triggers pain responses via the upregulation of C-C motif chemokine 22(CCL22) in macrophages while blocking the CCL22 receptor C-C motif chemokine receptor 4 (CCR4) attenuates pain hypersensitivity. Taken together, our findings indicate that the G-protein-coupled receptor 183-CCL22 axis has a critical role in the development and maintenance of inflammatory pain. [Display omitted] [ABSTRACT FROM AUTHOR]

ABSTRACT Toxoplasma gondii is a major source of congenital disease worldwide, but the cellular and molecular factors associated with its vertical transmission are largely unknown. In humans, the placenta forms the key interface between the maternal and fetal compartments and forms the primary barrier that restricts the hematogenous spread of microorganisms. Here, we utilized primary human trophoblast (PHT) cells isolated from full-term placentas and human midgestation chorionic villous explants to determine the mechanisms by which human trophoblasts restrict and respond to T. gondii infection. We show that placental syncytiotrophoblasts, multinucleated cells that are in direct contact with maternal blood, restrict T. gondii infection at two distinct stages of the parasite lytic cycle—at the time of attachment and also during intracellular replication. Utilizing comparative transcriptome sequencing (RNA-seq) transcriptional profiling, we also show that human placental trophoblasts from both the second and third trimesters respond uniquely to T. gondii infection compared to trophoblast cell lines, typified by the upregulation of several immunity-related genes. One of the most differentially induced genes was the chemokine CCL22, which relies on the secretion of a parasite effector(s) either during or after invasion for its induction. Collectively, our findings provide new insights into the mechanisms by which the human placenta restricts the vertical transmission of T. gondii at early and late stages of human pregnancy and demonstrate the existence of at least two interferon-independent pathways that restrict T. gondii access to the fetal compartment. IMPORTANCE Toxoplasma gondii is a major source of congenital disease worldwide and must breach the placental barrier to be transmitted from maternal blood to the developing fetus. The events associated with the vertical transmission of T. gondii are largely unknown. Here, we show that primary human syncytiotrophoblasts, the fetus-derived cells that comprise the primary placental barrier, restrict T. gondii infection at two distinct stages of the parasite life cycle and respond to infection by inducing a unique immunomodulatory transcriptional profile. Collectively, our findings provide important insights into the mechanisms by which human syncytiotrophoblasts restrict T. gondii infection at early and late stages of human pregnancy, identify both permissive and resistant human placental cell types, and identify the placenta-enriched signaling pathways induced in response to infection.

Many different therapeutic strategies focus on targeting tumor-associated macrophages (TAMs), due to their vital role in creating an immune suppressive tumor microenvironment (TME) with the aim to deplete, reprogram or target the functional mediators secreted by these cells. Immune modulatory vaccination is an emerging strategy to target immune suppressive myeloid populations in the TME. In contrast to the other clinical strategies that target TAMs, this combines both TAM depletion (through direct killing by cytotoxic T cells) and TAM reprogramming (by introducing pro-inflammatory cytokines into the immune suppressive microenvironment).

Objective: Previous studies have indicated a decrease in T regulatory cells (Tregs) among patients with steroid-resistant nephrotic syndrome. CCL22 and Leptin influenced the immune function of Tregs through their respective pathways. This study aimed to compare patients with steroid-sensitive nephrotic syndrome (SSNS) and steroid-resistant nephrotic syndrome (SRNS) in terms of CCL22 and Leptin levels., Methods: This prospective study included 117 children diagnosed with idiopathic nephrotic syndrome (INS). Peripheral blood samples were collected before initiating steroid therapy, and serum levels of CCL22 and Leptin were measured. Patients were categorized into three groups based on their response to steroid treatment. Renal biopsies were recommended for all children diagnosed with INS, with higher acceptance rates in glucocorticoid resistance patients., Results: Based on the response to steroid treatment, 117 children were divided as groups of SSNS (82 cases), frequent relapse nephrotic syndrome (FRNS) (10 cases), and SRNS (25 cases). A total of 41 patients underwent kidney biopsy, 11 cases (13.4%) in SSNS, 7 cases (70.0%) in FRNS and 24 cases (96.0%) in SRNS. 30 cases were minimal change disease (MCD), 9 cases were mesangial proliferative glomerulonephritis (MsPGN) and 3 cases were focal segmental glomerulosclerosis (FSGS). The levels of Leptin were significantly higher in SR patients (1208.1 ± 1044.1 pg/ml) compared to SS patients (515.4 ± 676.9 pg/ml) and controls (507.9 ± 479.8 pg/ml), regardless of the pathological type. CCL22 levels were significantly elevated in SRNS (92.2 ± 157.0 pg/ml), but the difference seemed to be attributed to the specific type of pathology, such as Minimal change disease (MCD) (127.4 ± 206.7 pg/ml) and focal segmental glomerulosclerosis (FSGS) (114.8 ± 22.0 pg/ml). For SRNS prediction, the AUC of Leptin, CCL22, and the joint prediction index were 0.764, 0.640, and 0.806, respectively., Conclusion: Serum levels of CCL22 and Leptin, detected prior to steroid therapy, were associated with steroid resistance in childhood INS., 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., (© 2023 Zhaoyang, Wei, Yanyan, Wenqing, Haidong and Jianhua.)

Minocycline/tetracycline is clinically used for the treatment of bullous pemphigoid (BP), and its clinical benefits are superior to those of prednisolone when considering adverse events. Although the clinical benefits of minocycline/tetracycline are well known, its immunosuppressive mechanisms are still unclear. In this study, we investigated the immunomodulatory effects of traditional anti‐BP drugs (minocycline, nicotinic acid amide, dexamethasone and cyclosporine) on CD163+ M2 macrophages in vitro, with special focus on the production of CCL18 and CCL22, both of which are produced by CD163+ M2 macrophages in the lesional skin of BP and are increased in the serum of BP patients. Minocycline decreased the production of CCL22, CCL24 and CCL26 as well as CCL2 from M2 macrophages. CCL18 from M2 macrophages was decreased by dexamethasone and cyclosporine, but not decreased by minocycline. These data suggest that the clinical benefit of minocycline is partially explained by its suppressive effects against the production of specific Th2 chemokines from M2 macrophages, which should contribute to the recruitment of Th2 cells and eosinophils in the lesional skin of BP patients. [ABSTRACT FROM AUTHOR]

Background: Tonsillitis can promote the progression of IgA nephropathy (IgAN) by aggravating immunopathologic response. Th22 cell disorder is involved in the pathogenesis of IgAN with tonsillitis. This study was determined to explore the possible mechanism of IgAN with tonsillitis underlying Th22 cell chemotaxis response to the effect of CCL20, CCL22, and CCL27.Methods: This research was conducted on 65 subjects including 16 healthy controls (HC group), 5 patients with  renal carcinoma (HTC group) and 44 patients with IgAN between 2015 and 2016. According to clinical symptoms and results of throat swab culture, patients with IgAN were divided into two groups: IgAN with tonsillitis (IgAN + tonsillitis, n = 14) and IgAN patients without tonsillitis (IgAN, n = 30). Distribution of Th22 cells in IgAN patients was determined. The expression of CCL20, CCL22, and CCL27 in both peripheral blood and kidneys of IgAN patients was investigated. Severity of pathological lesions in IgAN patients was analyzed. Coculture assay and transwell assay were performed to explore the impacts of human mesangial cells (HMC) on Th22 cell chemotaxis and Th22 cell local accumulation under hemolytic streptococcus (HS) infection.Results: Th22 cell percentages in IgAN patients increased compared with healthy controls. This increased Th22 cell percentage was positively correlated with the renal lesions of IgAN patients. Correspondingly, the expression of CCL20, CCL22, and CCL27 in renal tissue increased in IgAN patients. Tonsillitis exacerbated these overrepresentations of Th22 cells and chemokines. It was found that HMC could produce CCL20, CCL22, and CCL27. The supernatant of HMC was chemotactic for Th22 cells. This activity of HMC was stimulated by HS infection, whereas treatment of anti-CCL20, anti-CCL22, and anti-CCL27 antibodies partly blocked this chemoattractant effect of HMC.Conclusions: Tonsil infection may aggravate the renal pathological lesions of IgAN by exacerbating Th22 cell accumulation. Our data suggested a collaboration between HMC and Th22 cells in IgAN with tonsillitis underlying the effects of CCL20, CCL22, and CCL27. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is a common inflammatory skin disease. Recent studies have revealed the involvement of T helper (Th)2 cytokines including Interleukin 4 (IL-4) in the pathogenesis of AD. Since epidermal Langerhans cells (LCs) and dermal myeloid dendritic cells (DCs) produce CCL17 and CCL22 that chemoattract Th2 cells, interfering with CCL17 and CCL22 production from LCs and dermal myeloid DCs may be beneficial in the treatment of AD. To investigate this, we stimulated murine bone marrow-derived DCs (BMDCs) with IL-4. IL-4 stimulation produced Ccl17 and Ccl22, which was attenuated by soybean tar Glyteer, a known aryl hydrocarbon receptor (Ahr) activator. Notably, Glyteer treatment blocked the nuclear translocation of Stat6 induced by IL-4 stimulation, suggesting that this treatment impairs the IL-4/Stat6 signaling pathway in BMDCs. Unexpectedly, Glyteer treatment did not potently upregulate the expression of Cyp1a1, a specific Ahr-responsive gene, suggesting that its inhibitory machinery for Ccl17 and Ccl22 expression is likely to operate in an Ahr-independent manner. These findings indicate that Glyteer may exhibit therapeutic potential for AD by downregulating the CCL17 and CCL22 production from DCs in a Th2-deviated microenvironment. [ABSTRACT FROM AUTHOR]

We investigated expressions of −CC chemokine ligand 2 (CCL2) and CCL5 in tumor samples from 147 breast cancer (BCa) patients and correlated with transforming growth factor-β (TGF-β) expression. We observed an inverse correlation of TGF-β expression with CCL2, CCL5 expression in early stages of BCa. On contrary, in late stages, CCL2, not CCL5, expression was found to be directly proportional with TGF-β expression. TGF-β stimulated MDA-MB-231 cells to express CCL2, however, downregulated both CCL2 and CCL5 in MCF-7. Interestingly, a significant swing of Th1-Th2 ratio towards Th2 is seen within the primary tumors expressing moderate/high-CCL2-low/negative-CCL5. We observed that CCL2-CCR2 interaction induces monocytes/macrophages to secrete Th2-attracting chemokine CCL22 in vitro . Therefore, CCL2 secreted from the tumor microenvironment may attract and interact with monocytes/macrophages, and favor Th2 accumulation by inducing CCL22 secretion. Study in 4T1-BALB/c BCa mouse model demonstrated significant ( p < 0.05) decrease in CCL2, CCL5 and CCL22 levels and reduction in lung metastatic nodule numbers upon administering TGF-β inhibitor. These findings collectively indicate that TGF-β regulates CCL2 and CCL5 expression in a stage-dependent manner during BCa progression, which in turn, determines Th1-Th2 balance within the tumor microenvironment. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). It affects more than two million people worldwide, mainly young adults, and may lead to progressive neurological disability. Chemokines and their receptors have been shown to play critical roles in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), a murine disease model induced by active immunization with myelin proteins or transfer of encephalitogenic CD4+ T cells that recapitulates clinical and neuropathological features of MS. Chemokine ligand-receptor interactions orchestrate leukocyte trafficking and influence multiple pathophysiological cellular processes, including antigen presentation and cytokine production by dendritic cells (DCs). The C-C class chemokines 17 (CCL17) and 22 (CCL22) and their C-C chemokine receptor 4 (CCR4) have been shown to play an important role in homeostasis and inflammatory responses. Here, we provide an overview of the involvement of CCR4 and its ligands in CNS autoimmunity. We review key clinical studies of MS together with experimental studies in animals that have demonstrated functional roles of CCR4, CCL17, and CCL22 in EAE pathogenesis. Finally, we discuss the therapeutic potential of newly developed CCR4 antagonists and a humanized anti-CCR4 antibody for treatment of MS. [ABSTRACT FROM AUTHOR]

Crohn's disease (CD) and ulcerative colitis (UC) are the most widely known types of inflammatory bowel diseases (IBD) and have been paid more attention due to their increasing incidence and a substantial increase in the risk of colorectal cancer (CRC). However, the phenotype and, more importantly, the function in the regulation of mucosal inflammation by different macrophages are poorly understood, even though macrophages constitute a major subset of intestinal myeloid cells. The results firstly showed that the subset of peritoneal CD11bCD169 macrophages increased and CCL22 expression level decreased significantly during the DSS-induced colitis. DSS-induced colitis was alleviated in CD169-DTR mice at least partially due to the deletion CD169 macrophages. Moreover, the CCL22 expression level in peritoneal macrophages from CD169-DTR mice was much higher than that from WT mice with DSS-induced colitis. And, the cell-sorting result revealed that CD11bCD169 macrophage cells did not express CCL22 dominantly. Further experiment in vivo demonstrated that treatment with recombinant murine CCL22 (rmCCL22) ameliorated the clinical symptoms of DSS-induced colitis. All these data indicated that macrophage subset of CD11bCD169 from peritoneal cavity played critical role probably together with low levels of CCL22 in DSS-induced colitis. [ABSTRACT FROM AUTHOR]

Dry eye disease (DED) is a common ocular disorder affecting millions of individuals worldwide. The pathology of DED involves the infiltration of CD4 + lymphocytes, leading to tear film instability and destructive inflammation. In the healthy steady state, a population of immunosuppressive T-cells called regulatory T-cells (Treg) regulates proliferation of immune cells that would otherwise lead to a disruption of immunological homeostasis. For this reason, it has been suggested that Tregs could restore the immunological imbalance in DED. To this end, one possible approach would be to recruit the body's own, endogenous Tregs in order to enrich them at the site of inflammation and tissue destruction. Previously, we have demonstrated a reduction of inflammation and disease symptoms in models of periodontitis corresponding to recruitment of endogenous Tregs, which was accomplished by local placement of controlled release systems that sustain a gradient of the chemokine CCL22, referred to here as Treg-recruiting microspheres. Given that DED is characterized by a pro-inflammatory environment resulting in local tissue destruction, we hypothesized that the controlled release of CCL22 could also recruit Tregs to the ocular surface potentially mediating inflammation and symptoms of DED. Indeed, data suggest that Treg-recruiting microspheres are capable of overcoming the immunological imbalance of Tregs and CD4 + IFN-γ + cells in the lacrimal gland. Administration of Treg-recruiting microspheres effectively mitigated the symptoms of DED as measured through a number of outcomes such as tear clearance, goblet cells density and corneal epithelial integrity, suggesting that recruitment of endogenous Treg can mitigate inflammation associated with DED. [ABSTRACT FROM AUTHOR]

Background Gastric cancer is a common cancer with a poor prognosis. Chemokines play important roles in the tumor microenvironments to support tumor growth and metastasis. The effects of C-C motif chemokine ligand 22 (CCL22) in gastric cancer remain unclear. Materials and methods Between January 1, 2014 and April 31, 2014, a total of 298 gastric cancer patients were recruited to this study. Circulating concentrations of CCL22 were measured in gastric cancer patients before surgery, at discharged and during follow-up visits. The expression of CCL22 in gastric cancer tumor beds was measured by immunohistochemistry. The proportion of CD3 + CD4 + CD25 + Foxp3 + regulatory T cells in tumor sites was assessed by flow cytometry. Results Gastric cancer patients had higher serum CCL22 levels compared to healthy controls ( P < 0.001). Immunohistochemistry indicated that the gastric cancer tumor beds were the source of serum CCL22, as gastric cancer patients had an increased proportion of strong expression of CCL22 ( P < 0.01), and immunohistochemistry scores were positively correlated with levels of circulating CCL22 ( P < 0.001). Gastric cancer tissue harbored a higher percentage of regulatory T cells compared to normal tumor-free stomach margins ( P < 0.001), and this abundance of regulatory T cells was positively correlated with circulating levels of CCL22 ( P < 0.001). Gastric cancer patients with peritoneal metastasis showed increased levels of circulating CCL22 before surgery compared to metastasis-free patients ( P < 0.001). Gastric cancer patients with the recurrence within the first year after surgery had elevated serum CCL22 concentrations at different time points compared to those of recurrence-free patients ( P < 0.001). Logistic regression analysis indicated that high CCL22 circulating levels before surgery is a risk factor for peritoneal metastasis and an independent risk factor for an early recurrence after surgery. Conclusions CCL22 plays an important role in supporting gastric cancer development presumably by increasing the percentage of regulatory T cells in the tumor microenvironments. CCL22 levels in sera have a predictive value for gastric cancer peritoneal metastasis and the early recurrence. Therefore, CCL22 may be a therapeutic target for gastric cancer. [ABSTRACT FROM AUTHOR]

Chemokines are critical players in the local immune responses to tumors. CCL17 (thymus and activation-regulated chemokine, TARC) and CCL22 (macrophage-derived chemokine, MDC) can attract CCR4-bearing cells involving the immune landscape of cancer. However, their direct roles and functional states in tumors remain largely unclear. We analyzed the lymphoma-related scRNA-seq and bulk RNA-seq datasets and identified the CCL17/CCL22-CCR4 axis as the unique participant of the tumor microenvironment. Then we edited the A20 lymphoma cell line to express CCL17 and CCL22 and assessed their function using three mouse models (Balb/C mouse, Nude mouse, and NSG mouse). In addition, we retrospectively checked the relationship between the CCL17/CCL22-CCR4 axis and the survival rates of cancer patients. The active CCL17/CCL22-CCR4 axis is a distinctive feature of the Hodgkin lymphoma microenvironment. CCR4 is widely expressed in immune cells but highly exists on the surface of NK, NKT, and Treg cells. The tumor model of Balb/C mice showed that CCL17 acts as an anti-tumor chemokine mediated by activated T cell response. In addition, the tumor model of Nude mice showed that CCL17 recruits NK cells for inhibiting lymphoma growth and enhances the NK-cDC1 interaction for resisting IL4i1-mediated immunosuppression. Interestingly, CCL17-mediated antitumor immune responses depend on lymphoid lineages but not mainly myeloid ones. Furthermore, we found CCL17/CCL22-CCR4 axis cannot be regarded as biomarkers of poor prognosis in most cancer types from the TCGA database. We provided direct evidence of antitumor functions of CCL17 mediated by the recruitment of conventional T cells, NKT cells, and NK cells. Clinical survival outcomes of target gene (CCL17 , CCL22 , and CCR4) expression also identified that CCL17/CCL22-CCR4 axis is not a marker of poor prognosis. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effect of baicalin on the growth of extranodal NK/T cell lymphoma (ENKTCL) cells and its related mechanism., Methods: Normal NK cells and human ENKTCL cells lines SNK-6 and YTS were cultured, then SNK-6 and YTS cells were treated with 5, 10, 20 μmol/L baicalin and set control. Cell proliferation and apoptosis was detected by Edu method and FCM method, respectively, and expressions of BCL-2, Bax, FOXO3 and CCL22 proteins were detected by Western blot. Interference plasmids were designed and synthesized. FOXO3 siRNA interference plasmids and CCL22 pcDNA overexpression plasmids were transfected with PEI transfection reagent. Furthermore, animal models were established for validation., Results: In control group and 5, 10, 20 μmol/L baicalin group, the proliferation rate of SNK-6 cells was (56.17±2.96)%, (51.92±4.63)%, (36.42±1.58)%, and (14.60±2.81)%, respectively, while that of YTS cells was (58.85±2.98)%, (51.38±1.32)%, (34.75±1.09)%, and (15.45±1.10)%, respectively. In control group and 5, 10, 20 μmol/L baicalin group, the apoptosis rate of SNK-6 cells was (5.93±0.74)%, (11.78±0.34)%, (28.46±0.44)%, and (32.40±0.37)%, respectively, while that of YTS cells was (7.93±0.69)%, (16.29±1.35)%, (33.91±1.56)%, and (36.27±1.06)%, respectively. Compared with control group, the expression of BCL-2 protein both in SNK-6 and YTS cells decreased significantly ( P <0.001), and the expression of Bax protein increased in SNK-6 cells only when the concentration of baicalin was 20 μmol/L ( P <0.001), while that in YTS cells increased in all three concentrations(5, 10, 20 μmol/L) of baicalin ( P <0.001). The expression of FOXO3 protein decreased while CCL22 protein increased in ENKTCL cell lines compared with human NK cells ( P <0.001), but the expression of FOXO3 protein increased ( P <0.01) and CCL22 protein decreased after baicalin treatment ( P <0.001). Animal experiments showed that baicalin treatment could inhibit tumor growth. The expression of CCL22 protein in ENKTCL tissue of nude mice treated with baicalin decreased compared with control group ( P <0.01), while the FOXO3 protein increased ( P <0.05). In addition, FOXO3 silencing resulted in the decrease of FOXO3 protein expression and increase of CCL22 protein expression ( P <0.01, P <0.001)., Conclusion: Baicalin can inhibit proliferation and promote apoptosis of ENKTCL cell lines SNK-6 and YTS, up-regulate the expression of Bax protein, down-regulate the expression of BCL-2 protein, and down-regulate the expression of CCL22 protein mediated by FOXO3 . Animal experiment shown that the baicalin can inhibit tumor growth. Baicalin can inhibit the growth and induce apoptosis of ENKTCL cells through FOXO3 / CCL22 signaling pathway.