Seasonal distribution and correlation between IL-10 and IL-13 gene polymorphism and their expression in scabies-infected patients.

Scabies is a significant concern in global health. It is more prevalent in individuals who have poor hygiene and live in crowded conditions, hence, it is seasonal distribution and immunological response in Erbil population is the aim of the present study. In the Erbil Dermatology Education Centre in Erbil, Iraq, 154 patients were recruited for the research between April 2022 and March 2023. If a patient has a suspicious skin lesion and itching for a minimum of one week, scabies may be considered. Blood samples were collected from each participant in the study to evaluate serum levels of IL-10 and IL-13, then the DNA was isolated to study the gene polymorphism for the mentioned cytokines. Results showed that female 60.3% were more infected than male 39.6%. The median age of participants was (10 - >51) years, among infested, adolescents aged 10-20 years displayed the highest rate (31.8%). The carriers of GA genotype of IL-10 were protective against the infection, OR:0.61. while the TT carriers of IL-13 were susceptible to scabies infection with OR:2.14. IL-10 GA genotype was more prevalent in male patients OR:2.14 whereas the AA genotype was most protective in females OR:0.32. the IL-13 CT genotype was protective for males with OR:0.52. Both of IL-10 and IL-13 serum levels were increased significantly with infection and highest levels were found in wild homozygous genotypes (GG and CC) and lowest ratio was found in mutant homozygous genotypes of IL-10 and IL-13 respectively. Point mutation in IL-10 GA was protective and wild TT genotype of IL-13 was susceptible to the scabies infection. Double mutation in IL-10 AA was protective to females and single mutation of IL-13 CT was protective to males.

Perivascular Adipose Tissue Becomes Pro-Contractile and Remodels in an IL10-/- Colitis Model of Inflammatory Bowel Disease.

Inflammatory Bowel Diseases (IBDs) are associated with aberrant immune function, widespread inflammation, and altered intestinal blood flow. Perivascular adipose tissue (PVAT) surrounding the mesenteric vasculature can modulate vascular function and control the local immune cell population, but its structure and function have never been investigated in IBD. We used an IL10-/- mouse model of colitis that shares features with human IBD to test the hypothesis that IBD is associated with (1) impaired ability of PVAT to dilate mesenteric arteries and (2) changes in PVAT resident adipocyte and immune cell populations. Pressure myography and electrical field stimulation of isolated mesenteric arteries show that PVAT not only loses its anti-contractile effect but becomes pro-contractile in IBD. Quantitative immunohistochemistry and confocal imaging studies found significant adipocyte hyperplasia and increased PVAT leukocytes, particularly macrophages, in IBD. PCR arrays suggest that these changes occur alongside the altered cytokine and chemokine gene expression associated with altered NF-κB signaling. Collectively, these results show that the accumulation of macrophages in PVAT during IBD pathogenesis may lead to local inflammation, which ultimately contributes to increased arterial constriction and decreased intestinal blood flow with IBD.

Event-free survival in neuroblastoma with MYCN amplification and deletion of 1p or 11q may be associated with altered immune status.

BACKGROUND: Neuroblastoma exhibits substantial heterogeneity, which is intricately linked to various genetic alterations. We aimed to explore immune status in the peripheral blood and prognosis of patients with neuroblastoma with different genetic characteristics. METHODS: We enrolled 31 patients with neuroblastoma and collected samples to detect three genetic characteristics. Peripheral blood samples were tested for immune cells and cytokines by fluorescent microspheres conjugated with antibodies and flow cytometry. Event-free survival (EFS) was analyzed using the Kaplan‒Meier method. RESULTS: Twenty-two patients had genetic aberrations, including MYCN amplification in 6 patients, chromosome 1p deletion in 9 patients, and chromosome 11q deletion in 14 patients. Two genetic alterations were present in seven patients. The EFS was worse in patients with MYCN amplification or 1p deletion than in the corresponding group, whereas 11q deletion was a prognostic factor only in patients with unamplified MYCN. Changes in immune status revealed a decrease in the proportion of T cells in blood, and an increase in regulatory T cells and immunosuppression-related cytokines such as interleukin (IL)-10. The EFS of the IL-10 high-level group was lower than that of the low-level group. Patients with concomitant genetic alterations and a high level of IL-10 had worse EFS than other patients. CONCLUSIONS: Patients with neuroblastoma characterized by these genetic characteristics often have suppressed T cell response and an overabundance of immunosuppressive cells and cytokines in the peripheral blood. This imbalance is significantly associated with poor EFS. Moreover, if these patients show an elevated levels of immunosuppressive cytokines such as IL-10, the prognosis will be worse.

Host cytokine genetic polymorphisms in a selected population of persons living with hepatitis B virus infection in the central region of Ghana.

BACKGROUND: Hepatitis B virus (HBV) infection is a public health concern in resource limited settings like Ghana. Over the past decades, it is noted that the natural course of HBV in persons infected are taking a worse turn leading to liver cirrhosis and cancer. The outcome of HBV infection is influenced by viral and host factors including genetics. Cytokine variations affect virus survival and progression and may even influence associated complications. Cytokines such as tumor necrosis factor alpha (TNF-α), interleukins (IL-4, IL-6, IL-8, IL-10, IL-18), interferon gamma (IFN)-γ, and tumor growth factor-beta (TGF-ß) have key roles in HBV infection and modulation. In this study, polymorphisms occurring in five cytokines were analysed to understand how they can influence prognosis of HBV infection. METHODS: The study is a single centre cross-sectional study involving 227 participants made up of HBV infected participants and HBV-negative controls. Recruitment was from March 2021 to April 2022. Blood samples were taken for full blood count, HBV antigen profile, liver function tests, HBV DNA quantification and cytokine genotyping. FIB score was calculated using available tools. Statistical analysis was undertaken with p < 0.05 set as statistically significant. RESULTS: The 20-39-year-old group formed majority of the HBV infected participants with 60% of all participants being classified as healthy HBsAg carriers. IL2 rs1479920 GG carriers ((1258.93; 0.00-5011.87) IU/mL had reduced HBV DNA in comparison to IL2 rs1479920 AA ((5011.87; 2113.49-5956.62) /AG (3548.13; 0.00-6309.57) IU/mL carriers. TNF-α rs1800629 AA carriers (1258.93; 0.00-3981.07) IU/mL had a reduction in HBV DNA levels in comparison to TNF-α rs1800629 GG carriers (1584.89; 0.00-5011.87) IU/mL. The results of univariate (OR = 0.08, 0.00-0.93; p = 0.043) and multivariate (OR = 0.02, 0.00-0.67; p = 0.029) analysis, showed that carrying TNF-α rs1800629 AA genotype reduce susceptibility to high FIB score compared with GG genotypes. In univariate analysis, subjects aged 20-39 years (OR = 5.00, 1.13-6.10; p = 0.034) and 40-59 years (OR = 41.99, 3.74-47.21; p = 0.0002) were more susceptible to high FIB score compared to subjects aged 1-19 years. Being female (OR = 2.42, 1.03-5.71; p = 0.043) in the univariate models showed higher odds of having high levels of HBV DNA in the multivariate model. There was a reduced likelihood of herbal medicine usage influencing HBV DNA levels significantly (OR = 0.29, 0.10-0.86; p = 0.025). CONCLUSION: In conclusion, variations in IL2 rs1479920 GG and IL2 rs1479921 AA could offer protective effects by reducing HBV DNA. TNF-α rs179924CT may also cause elevation in HBV DNA levels whiles TNF-α -308A/G, showed a potential protective effect on liver scarring in HBV infected participants. It is therefore important to take a further look at such variations for understanding of HBV modulation in the Ghanaian population.

Cytokine gene polymorphisms and suicide risk in an Indian ancestral population: A case-control study.

BACKGROUND: India currently accounts for a majority of global suicide deaths. Research in European ancestry has established that suicide mortality has a significant genetic component, and suggests that inflammation may play a crucial role in the pathophysiology of suicide. Inflammation is also highly relevant in regions of increased pollution exposure, such as the megacities of India. To address the existing gaps in genetic research on suicide and possible association with inflammatory biomarkers, we examined genetic polymorphism and clinical risk phenotypes in a population-based suicide-death cohort, India. MATERIAL AND METHODS: Genotyping of IL-1ß(rs16944) & (rs1143627), IL-4(rs2070874), IL-6(rs1800795) and IL-10(rs1800896) was done in 234 post-mortem suicide-death cases and 256 post-mortem controls (N = 490) using PCR RFLP method. RESULTS: Our analyses identified three significant (p < 0.001) associations of cytokine variants with suicide death, including IL-1ß(rs16944), OR = 0.627; IL-4(rs2070874), OR = 0.524; and IL-6(rs1800795), OR = 2.509. Cases were more likely female and were more likely to have a history of psychiatric illness, though rate of psychiatric illness was low in suicide cases(9%). CONCLUSION: Our genetic results are generally consistent with previous research on risk for depression and suicidal behaviour, and both genetic and phenotypic results provide new insights into risk factors that may contribute to suicide in India.

Immune-enhancing effect of Weizmannia coagulans BCG44 and its supernatant on cyclophosphamide-induced immunosuppressed mice and RAW264.7 cells via the modulation of the gut microbiota.

We established a model of cyclophosphamide (CTX)-induced immunosuppressed mice and RAW264.7 cells to assess the effectiveness of W. coagulans BCG44 and its supernatant in enhancing immune function and modulating the gut microbiota. W. coagulans BCG44 and its supernatant restored Th17/Treg balance and alleviated gut inflammation by elevating the expression of interleukin-10 (IL-10) and decreasing IL-6 and toll-like receptor 4 (TLR4). Meanwhile, W. coagulans BCG44 and its supernatant downregulated the levels of lipopolysaccharide and D-lactic acid while increasing the expression of tight junction proteins (ZO-1 and occludin) and goblet cells/crypts to ameliorate mucosal damage. W. coagulans BCG44 and its supernatant may restore the gut microbiota in the immunosuppressed mice by regulating keystone species (Lactobacillus and Lachnospiraceae). PICRUSt2 function prediction and BugBase analysis showed that W. coagulans BCG44 and its supernatant significantly down-regulated American trypanosomiasis and potentially_pathogenic. In addition, under normal versus inflamed culture conditions, stimulation of RAW246.7 cells with W. coagulans BCG44 supernatant activated immune response with increasing proliferation ability and the gene expression of IL-10 while decreasing TLR4. Metabolites in the W. coagulans BCG44 supernatant included arginine, tyrosine, solamargine, tryptophan, D-mannose, phenyllactic acid, and arachidonic acid. Collectively, these findings suggested that W. coagulans BCG44 and its supernatant possess potential immunomodulatory activity and modulate gut microbiota dysbiosis in the CTX-induced immunosuppressed mice.

Exploring the Role of miR-132 in Rat Bladders and Human Urothelial Cells during Wound Healing.

Urinary bladder wound healing shares many features with skin healing, involving several molecular players, including microRNAs (miRs). This study investigated the role of miR-132 in urothelial cells. We analyzed miR-132 expression in rat bladder using in situ hybridization and conducted gain and loss of miR-132 function assays in primary human urothelial cells (HUCs). These assays included cell proliferation and migration studies. To explore the regulation of miR-132 expression, cells were treated with wound-healing-related factors such as interleukin 6 (IL-6), interleukin 10 (IL-10), and transforming growth factor beta-1 (TGF-ß1). Predictive bioinformatics and a literature review identified potential miR-132 targets, which were validated through real-time polymerase chain reaction (RT-PCR) and Western blot analysis. miR-132 was found to promote cellular proliferation and migration during the early stages of urothelial wound repair. Its expression was modulated by key cytokines such as IL-6, IL-10, and TGF-ß1. miR-132 played a crucial role in urothelial wound healing by enhancing cell proliferation and migration, regulated by cytokines, suggesting its action within a complex regulatory network. These findings highlight the therapeutic potential of targeting miR-132 in bladder injury repair, offering new insights into bladder repair mechanisms.

Recombinant ISRAA ameliorates imiquimod-induced psoriasis and knocking out Israa delays its onset.

Psoriasis, an inflammatory disease, is largely mediated by T-helper 17 cytokines. We have previously identified the immune system-released activating agent (Israa) as a novel gene that connects the nervous and immune systems. This research aims to investigate the role of the Israa gene in psoriasis in vivo using the imiquimod-induced psoriasis model. We established the model in C57BL/6 wildtype mice, which were then treated with 200 pg/mouse, 400 pg/mouse, or 800 pg/mouse of recombinant ISRAA compared to methotrexate. Subsequently, we also induced psoriasis in Israa-knockout mice to confirm the effect of Israa. Results consistently showed improvement in psoriasis in all groups receiving recombinant ISRAA. The 200 pg/mouse dose eliminated the disease, reduced the cutaneous release of IL-17 to one-third and TNF-α to one-sixth, increased IL-10 release to over 500 pg, completely resolved parakeratosis, decreased epidermal thickness to one-half, and reduced the expression of CD4 and neutrophil elastase in the skin (all p < 0.05). Israa-knockout mice exhibited less severe psoriasis in all scoring, biochemical, and histological parameters compared to wild-type mice (p < 0.05). This study highlights Israa as a crucial molecule in psoriasis and confirms its immunomodulatory role in inflammatory diseases.

[Effects of moxibustion in improving synovitis in adjuvant arthritis rats by regulating synovial GPR43 and peripheral blood Th17/Treg balance]. / 艾灸通过调节滑膜G蛋白偶联受体43å’Œè¾ åŠ©æ€§T细胞17/调节性Tç»†èƒžå¹³è¡¡æ”¹å–„ä½å‰‚æ€§å ³èŠ‚ç‚Žå¤§é¼ æ»‘è†œç‚Žæ€§ååº”.

OBJECTIVES: To observe the effects of moxibustion on G protein-coupled receptor 43 (GPR43) and helper T cell 17 (Th17)/regulatory T cell (Treg) balance in rats with adjuvant arthritis (AA), so as to investigate the partial mechanism of moxibustion therapy on rheumatoid arthritis (RA). METHODS: A total of 24 Wistar rats were randomly divided into a normal group, a model group and a moxibustion group, with 8 rats in each group. The AA rat model was replicated using wind, cold and moisture environmental factors + Freund's complete adjuvant (CFA) injection method. In the moxibustion group, moxibustion was performed on bilateral "Zusanli" (ST36) and "Shenshu" (BL23) for 20 min/time, once daily, for 21 d. The changes of joint swelling degree (JSD) and arthritis index (AI) were observed in each group of rats. Transmission electron microscopy and HE staining were used to examine changes in the cellular structure of the ankle joint synovial tissue in each group. Western blot analysis was employed to detect the expression levels of GPR43 in the synovial tissue of the ankle joints. Flow cytometry was used to measure the percentages of Treg and Th17 in peripheral blood. ELISA was used to determine the contents of interleukin-10 (IL-10) and transforming growth factor-ß 1 (TGF-ß1) in serum. RESULTS: Compared with the normal group, the JSD and AI in the model group increased before and after treatment (P<0.01), with significant synovial pathological and ultrastruct ural injury observed. Additionally, compared with the normal group, the expression of GPR43 in the synovial tissue decreased (P<0.01), the Treg percentage in peripheral blood decreased (P<0.01) and the Th17 percentage increased (P<0.01), serum IL-10 and TGF-ß1 contents decreased in the model group (P<0.01). Compared with the model group, the moxibustion group exhibited a significant reduction in JSD and AI after treatment (P<0.01), the degree of pathological and ultrastruct ural damage in the synovium decreased, the expression of GPR43 in the synovial tissue increased (P<0.05), the Treg percentage in peripheral blood increased (P<0.01) and the Th17 percentage decreased (P<0.01), serum IL-10 and TGF-ß1 contents increased (P<0.01). The relative expression of GPR43 in synovial tissue was positively correlated with the percentage of Treg in peripheral blood (r=0.967, P<0.01). CONCLUSIONS: Moxibustion can significantly improve the inflammatory response in the synovial membrane of AA rats. The mechanism may be related to moxibustion restoring the Th17/Treg balance through regulating GPR43.

Predictive nomogram of the clinical outcomes of colorectal cancer based on methylated SEPT9 and intratumoral IL-10+ Tregs infiltration.

BACKGROUND: Gene methylation and the immune-related tumor microenvironment (TME) are highly correlated in tumor progression and therapeutic efficacy. Although both of them can be used to predict the clinical outcomes of colorectal cancer (CRC) patients, their predictive value is still unsatisfactory. Whether a combination risk model comprising these two prediction parameters performs better predictive effectiveness than independent factor is still unclear. Methylated Septin9 (mSEPT9) is an early diagnosis biomarker of CRC, in this study, we aimed to investigate mSEPT9-related biomarkers of immunosuppressive TME and identify the value of the combination risk model in predicting the clinical outcomes of CRC. METHODS: Immunofluorescence staining was performed to clarify the correlation between intratumoral IL-10+ Treg infiltration and mSEPT9 in peripheral blood. Survival time, response to 5-fluorouracil (5-FU)-based chemotherapy and PD-1 blockade, and the probability of recurrence or metastasis were analyzed in study (197 CRC samples) and validation (195 CRC samples) sets to evaluate the efficacy of combination risk model. Potential mechanisms were explored by mRNA sequencing. RESULTS: Hypermethylated SEPT9 in the peripheral blood of patients with CRC (stage I-III, and stage IV with resectable M1) before radical resection was positively correlated with high intratumoral IL-10+ Treg infiltration. The high-risk model revealed poor overall survival and progression-free survival, inferior therapeutic response to 5-FU-based chemotherapy and PD-1 blockade, and high probability of recurrence or metastasis. The underlying mechanisms may be associated with the increase in mSEPT9 and mediation of IL-10 via methionine metabolic reprogramming-induced infiltration of IL-10+ Tregs in the TME, which promotes tumor progression and resistance to 5-FU-based chemotherapy and PD-1 blockade. CONCLUSIONS: The combination risk model of peripheral mSETP9 and intratumoral IL-10+ Treg infiltration in CRC can effectively predict prognosis, responsiveness to 5-FU-based chemotherapy and PD-1 blockade, and the probability of recurrence or metastasis. Therefore, this model can be used for precision treatment of CRC.

Interleukin-10 overexpression in 4T1 cells: A gateway to suppressing mammary carcinoma growth.

Interleukin-10 (IL-10) exerts complex effects on tumor growth, exhibiting both pro- and anti-tumor properties. Recent focus on the anti-inflammatory properties of IL-10 has highlighted its potential anti-tumor properties, particularly through the enhancement of CD8+ T cell activity. However, further research is needed to fully elucidate its other anti-tumor mechanisms. Our study investigates novel anti-tumor mechanisms of IL-10 in a murine mammary carcinoma model (4T1). We found that IL-10 overexpression in mouse 4T1 cells suppressed tumor growth in vivo. This suppression was accompanied by an increase in IFN-γ-secreting CD8+ T cells and a decrease in myeloid-derived suppressor cells (MDSCs) in tumor tissue. In vitro experiments showed that IL-10-rich tumor cell-derived supernatants inhibited myeloid cell differentiation into monocytic and granulocytic MDSCs while reducing MDSCs migration. In addition, IL-10 overexpression downregulated CXCL5 expression in 4T1 cells, resulting in decreased CXCR2+ MDSCs infiltration. Using RAG1-deficient mice and CXCL5 knockdown tumor models, we demonstrated that the anti-tumor effects of IL-10 depend on both CD8+ T cells and reduced MDSC infiltration. IL-10 attenuated the immunosuppressive tumor microenvironment by enhancing CD8+ T cell activity and inhibiting MDSCs infiltration. In human breast cancer, we observed a positive correlation between CXCL5 expression and MDSC infiltration. Our findings reveal a dual mechanism of IL-10-mediated tumor suppression: (1) direct enhancement of CD8+ T cell activity and (2) indirect reduction of immunosuppressive MDSCs through CXCL5 downregulation and inhibition of myeloid cell differentiation. This study provides new insights into the role of IL-10 in anti-tumor immunity and suggests potential strategies for breast cancer immunotherapy by modulating the IL-10-CXCL5-MDSCs axis.

Variation in innate immune responses to porcine epidemic diarrhea virus infection in piglets at different ages.

Porcine epidemic diarrhea virus (PEDV) poses a significant threat to pigs, with piglets under seven days old facing a mortality rate of up to 100 %. This study aimed to explore the maturation of the immune system in piglets across different age groups and their corresponding immune responses to PEDV infection. Real-time quantitative PCR was employed to assess the relative mRNA expression of inflammation-related factors in infected pigs compared to non-infected counterparts at varying ages. Additionally, flow cytometry was utilized to analyze the relative counts of CD4+ and CD8+ T cells, as well as CD21+ B cells, in peripheral blood, spleen, mesenteric lymph nodes, and Peyer's patches of piglets at different developmental stages. Our findings revealed a notable increase in IFN-α and IFN-γ, a decrease in TNF-α, and elevated expression of IL-1ß, IL-6, IL-10, and IL-17 following PEDV infection. Furthermore, the numbers of CD4+ and CD8+ T cells, along with CD21+ B cells, exhibited a gradual rise with the advancement of piglets' age. Overall, our study underscores the progressive enhancement of piglets' resistance to PEDV infection as their immune system matures over time.

IL-10 A-Allele as a Biomarker for Periodontitis Severity in Bulgarian Patients.

BACKGROUND: Periodontitis is a complex disease, and bacterial factors play a crucial role in its initiation. The contributions of genetic and epigenetic factors to the pathogenesis of periodontal disease are increasingly recognized. Single-nucleotide polymorphisms (SNPs) in various molecules, including cytokines, are of particular interest due to their established involvement in numerous diseases. This study investigates the influence of SNPs in the IL-10 gene at positions -592 (rs1800872) C>A and -1082 (rs1800896) T>C (also referred to as 1082A>G) on the severity of periodontitis in a cohort of Bulgarian patients. METHODS: In the recent study, both clinical and paraclinical methodologies were employed to comprehensively assess the periodontal status of the participants. The genotypic characterization of IL-10 polymorphisms was performed by PCR RFLP analysis. Statistical analyses, including principal component analysis (PCA), were executed utilizing IBM SPSS Statistics Version 21. RESULTS: We have established a statistically significant association between the presence of at least one A-allele in the patients' genotype and the incidence of severe periodontitis (p = 0.047). CONCLUSIONS: IL-10 single-nucleotide polymorphisms (SNPs) could be effectively considered as biomarkers for the severity of periodontitis.

Relationship between HLA-II Gene Polymorphisms and Immune Response in COVID-19 Survivors and Volunteers Vaccinated against This Infection.

The polymorphism of HLA class II genes was studied in COVID-19 survivors and vaccinated people. Six allelic variants of DQA1, 10 of DQB1, and 11 of DRB1 were identified. The DQA1*05:01 allele predominated in vaccinated volunteers and the DQA1*02:01, *01:03, and DQB1*06:02-8 alleles predominated in convalescents. In the groups with DQA1*01:01, *05:01 and *06:01 alleles, a high proportion of individuals seropositive for SARS-CoV-2 S protein was found. In the group with DQA1*02:01 allele, 40% of volunteers were found to have IgM and a significantly lower quantity of IgG to N protein of coronavirus. Comparative analysis showed a statistically significant increase in IL-10 levels in carriers of the DQA1*01:01 allele, which may indicate the influence of this allele on cytokine production. Further study of the immune response indices and their association with HLA class II gene polymorphism will provide better understanding of the mechanisms of COVID-19 immunogenesis.

Fecal let-7b and miR-21 directly modulate the intestinal microbiota, driving chronic inflammation.

Inflammatory bowel diseases (IBD) etiology is multifactorial. Luminal microRNAs (miRNAs) have been suspected to play a role in the promotion of chronic inflammation, but the extent to which fecal miRNAs are interacting with the intestinal ecosystem in a way that contribute to diseases, including IBD, remains unknown. Here, fecal let-7b and miR-21 were found elevated, associated with inflammation, and correlating with multiple bacteria in IBD patients and IL-10-/- mice, model of spontaneous colitis. Using an in vitro microbiota modeling system, we revealed that these two miRNAs can directly modify the composition and function of complex human microbiota, increasing their proinflammatory potential. In vivo investigations revealed that luminal increase of let-7b drastically alters the intestinal microbiota and enhances macrophages' associated proinflammatory cytokines (TNF, IL-6, and IL-1ß). Such proinflammatory effects are resilient and dependent on the bacterial presence. Moreover, we identified that besides impairing the intestinal barrier function, miR-21 increases myeloperoxidase and antimicrobial peptides secretion, causing intestinal dysbiosis. More importantly, in vivo inhibition of let-7b and miR-21 with anti-miRNAs significantly improved the intestinal mucosal barrier function and promoted a healthier host-microbiota interaction in the intestinal lining, which altogether conferred protection against colitis. In summary, we provide evidence of the functional significance of fecal miRNAs in host-microbiota communication, highlighting their therapeutic potential in intestinal inflammation and dysbiosis-related conditions, such as IBD.

Local administration of regulatory T cells promotes tissue healing.

Regulatory T cells (Tregs) are crucial immune cells for tissue repair and regeneration. However, their potential as a cell-based regenerative therapy is not yet fully understood. Here, we show that local delivery of exogenous Tregs into injured mouse bone, muscle, and skin greatly enhances tissue healing. Mechanistically, exogenous Tregs rapidly adopt an injury-specific phenotype in response to the damaged tissue microenvironment, upregulating genes involved in immunomodulation and tissue healing. We demonstrate that exogenous Tregs exert their regenerative effect by directly and indirectly modulating monocytes/macrophages (Mo/MΦ) in injured tissues, promoting their switch to an anti-inflammatory and pro-healing state via factors such as interleukin (IL)-10. Validating the key role of IL-10 in exogenous Treg-mediated repair and regeneration, the pro-healing capacity of these cells is lost when Il10 is knocked out. Additionally, exogenous Tregs reduce neutrophil and cytotoxic T cell accumulation and IFN-γ production in damaged tissues, further dampening the pro-inflammatory Mo/MΦ phenotype. Highlighting the potential of this approach, we demonstrate that allogeneic and human Tregs also promote tissue healing. Together, this study establishes exogenous Tregs as a possible universal cell-based therapy for regenerative medicine and provides key mechanistic insights that could be harnessed to develop immune cell-based therapies to enhance tissue healing.

The Enigmatic Interplay of Interleukin-10 in the Synergy of HIV Infection Comorbid with Preeclampsia.

Cytokines coordinate the intricate choreography of the immune system, directing cellular activities that mediate inflammation, pathogen defense, pathology and tissue repair. Within this spectrum, the anti-inflammatory prowess of interleukin-10 (IL-10) predominates in immune homeostasis. In normal pregnancy, the dynamic shift of IL-10 across trimesters maintains maternal immune tolerance ensuring fetal development and pregnancy success. Unravelling the dysregulation of IL-10 in pregnancy complications is vital, particularly in the heightened inflammatory condition of preeclampsia. Of note, a reduction in IL-10 levels contributes to endothelial dysfunction. In human immunodeficiency virus (HIV) infection, a complex interplay of IL-10 occurs, displaying a paradoxical paradigm of being immune-protective yet aiding viral persistence. Genetic variations in the IL-10 gene further modulate susceptibility to HIV infection and preeclampsia, albeit with nuanced effects across populations. This review outlines the conceptual framework underlying the role of IL-10 in the duality of normal pregnancy and preeclampsia together with HIV infection, thus highlighting its regulatory mechanisms and genetic influences. Synthesizing these findings in immune modulation presents avenues for therapeutic interventions in pregnancy complications comorbid with HIV infection.

Autoimmunity-Associated SNP rs3024505 Disrupts STAT3 Binding in B Cells, Leading to IL10 Dysregulation.

Interleukin 10 (IL10) is a major anti-inflammatory cytokine that acts as a master regulator of the immune response. A single nucleotide polymorphism rs3024505(C/T), located downstream of the IL10 gene, is associated with several aggressive inflammatory diseases, including systemic lupus erythematosus, Sjögren's syndrome, Crohn's disease, and ulcerative colitis. In such autoimmune pathologies, IL10-producing B cells play a protective role by decreasing the level of inflammation and restoring immune homeostasis. This study demonstrates that rs3024505 is located within an enhancer that augments the activity of the IL10 promoter in a reporter system based on a human B cell line. The common rs3024505(C) variant creates a functional binding site for the transcription factor STAT3, whereas the risk allele rs3024505(T) disrupts STAT3 binding, thereby reducing the IL10 promoter activity. Our findings indicate that B cells from individuals carrying the minor rs3024505(T) allele may produce less IL10 due to the disrupted STAT3 binding site, contributing to the progression of inflammatory pathologies.

Downregulation of IL-8 and IL-10 by LRRC8A Inhibition through the NOX2-Nrf2-CEBPB Transcriptional Axis in THP-1-Derived M2 Macrophages.

M2-polarized, tumor-associated macrophages (TAMs) produce pro-tumorigenic and angiogenic mediators, such as interleukin-8 (IL-8) and IL-10. Leucine-rich repeat-containing protein 8 members (LRRC8s) form volume-regulated anion channels and play an important role in macrophage functions by regulating cytokine and chemokine production. We herein examined the role of LRRC8A in IL-8 and IL-10 expression in THP-1-differentiated M2-like macrophages (M2-MACs), which are a useful tool for investigating TAMs. In M2-MACs, the pharmacological inhibition of LRRC8A led to hyperpolarizing responses after a transient depolarization phase, followed by a slight elevation in the intracellular concentration of Ca2+. Both the small interfering RNA-mediated and pharmacological inhibition of LRRC8A repressed the transcriptional expression of IL-8 and IL-10, resulting in a significant reduction in their secretion. The inhibition of LRRC8A decreased the nuclear translocation of phosphorylated nuclear factor-erythroid 2-related factor 2 (Nrf2), while the activation of Nrf2 reversed the LRRC8A inhibition-induced transcriptional repression of IL-8 and IL-10 in M2-MACs. We identified the CCAAT/enhancer-binding protein isoform B, CEBPB, as a downstream target of Nrf2 signaling in M2-MACs. Moreover, among several upstream candidates, the inhibition of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2) suppressed the Nrf2-CEBPB transcriptional axis in M2-MACs. Collectively, the present results indicate that the inhibition of LRRC8A repressed IL-8 and IL-10 transcription in M2-MACs through the NOX2-Nrf2-CEBPB axis and suggest that LRRC8A inhibitors suppress the IL-10-mediated evasion of tumor immune surveillance and IL-8-mediated metastasis and neovascularization in TAMs.

IL-10 deficiency aggravates cell senescence and accelerates BLM-induced pulmonary fibrosis in aged mice via PTEN/AKT/ERK pathway.

BACKGROUND: Pulmonary fibrosis (PF) is an aging-related progressive lung disorder. The aged lung undergoes functional and structural changes termed immunosenescence and inflammaging, which facilitate the occurrence of fibrosis. Interleukin-10 (IL-10) is a potent anti-inflammatory and immunoregulatory cytokine, yet it remains unclear how IL-10 deficiency-induced immunosenescence participates in the development of PF. METHODS: Firstly we evaluated the susceptibility to fibrosis and IL-10 expression in aged mice. Then 13-month-old wild-type (WT) and IL-10 knockout (KO) mice were subjected to bleomycin(BLM) and analyzed senescence-related markers by PCR, western blot and immunohistochemistry staining of p16, p21, p53, as well as DHE and SA-ß-gal staining. We further compared 18-month-old WT mice with 13-month-old IL-10KO mice to assess aging-associated cell senescence and inflamation infiltration in both lung and BALF. Moreover, proliferation and apoptosis of alveolar type 2 cells(AT2) were evaluated by FCM, immunofluorescence, TUNEL staining, and TEM analysis. Recombinant IL-10 (rIL-10) was also administered intratracheally to evaluate its therapeutic potential and related mechanism. For the in vitro experiments, 10-week-old naïve pramily lung fibroblasts(PLFs) were treated with the culture medium of 13-month PLFs derived from WT, IL-10KO, or IL-10KO + rIL-10 respectively, and examined the secretion of senescence-associated secretory phenotype (SASP) factors and related pathways. RESULTS: The aged mice displayed increased susceptibility to fibrosis and decreased IL-10 expression. The 13-month-old IL-10KO mice exhibited significant exacerbation of cell senescence compared to their contemporary WT mice, and even more severe epithelial-mesenchymal transition (EMT) than that of 18 month WT mice. These IL-10 deficient mice showed heightened inflammatory responses and accelerated PF progression. Intratracheal administration of rIL-10 reduced lung CD45 + cell infiltration by 15%, including a 6% reduction in granulocytes and a 10% reduction in macrophages, and increased the proportion of AT2 cells by approximately 8%. Additionally, rIL-10 significantly decreased α-SMA and collagen deposition, and reduced the expression of senescence proteins p16 and p21 by 50% in these mice. In vitro analysis revealed that conditioned media from IL-10 deficient mice promoted SASP secretion and upregulated senescence genes in naïve lung fibroblasts, which was mitigated by rIL-10 treatment. Mechanistically, rIL-10 inhibited TGF-ß-Smad2/3 and PTEN/PI3K/AKT/ERK pathways, thereby suppressing senescence and fibrosis-related proteins. CONCLUSIONS: IL-10 deficiency in aged mice leads to accelerated cell senescence and exacerbated fibrosis, with IL-10KO-PLFs displaying increased SASP secretion. Recombinant IL-10 treatment effectively mitigates these effects, suggesting its potential as a therapeutic target for PF.