The effects of interleukin-35 and interleukin-10 on pulmonary inflammation and fibrosis in a bleomycin-induced systemic sclerosis mouse modelHuang, Zeng, Liao
et alClin Exp Rheumatol (2025)
Abstract: We investigated the impact of IL-35 and IL-10 on the immune response and pulmonary fibrosis using a bleomycin (BLM)-induced SSc mouse model.BLM was administered subcutaneously to Balb/c mice and either mouse recombinant (rm)IL-35, rmIL-10 or neutralising antibody of IL-35 and IL-10 was injected intraperitoneally after BLM administration. Lung fibrosis was assessed by the pathological alterations, hydroxyproline content, and the Collagen I and α-SMA mRNA expression. The expression of immune cells and their related factors were respectively measured by flow cytometry and ELISA. Western blot was used to measure STAT3 pathway expression.Compared with controls, BLM exposure induced increased Ashcroft ratings, hydroxyproline and lung collagen I and α-SMA expression, which was lessened by rmIL-35 or rmIL-10 intervention, while it did not change after blocking IL-35 and IL-10. BLM exposure increased IL-4 and IL-17A expression in bronchoalveolar lavage (BAL) supernatant, which was downregulated by rmIL-35 or rmIL-10 administration. Compared with BLM group, RmIL-35 and rmIL-10 group both downregulated Th2/nTreg and Th17/nTreg percentage, while increased Treg cell proportion in the spleen. Moreover, the spleen iTr35 cells ratio was negatively correlated with BAL supernatant IL-17A and IL-4 levels and lung collagen I and α-SMA expression. Further pathway analysis revealed that rmIL-35 administration decreased the phosphorylation of STAT3 compared with BLM group.Our findings suggest that IL-35 and IL-10 might alleviate pulmonary inflammation and fibrosis via upregulating the proportion of Treg cells and reducing BAL supernatant IL-17A and IL-4 levels in a bleomycin-induced SSc mouse model.
Immunomodulatory Effect of Rivaroxaban Nanoparticles Alone and in Combination with Sitagliptin on Diabetic Rat ModelElbadr, Galal, Hetta
et alDiseases (2025) 13 (3)
Abstract: Chronic inflammation and immune dysregulation are key drivers of diabetes complications. Rivaroxaban (RX) and sitagliptin (SITA) are established therapies for thromboembolism and glycemic control, respectively. This study evaluated the novel therapeutic potential of nano-rivaroxaban (NRX) alone and in combination with sitagliptin (SITA) in mitigating inflammation and restoring immune balance in streptozotocin (STZ)-induced diabetic rats.Type 2 diabetes was induced in rats using a single injection of STZ (60 mg/kg). Animals were divided into five groups: control, STZ-diabetic, RX-treated (5 mg/kg), NRX-treated (5 mg/kg), and NRX+SITA-treated (5 mg/kg + 10 mg/kg). After 4 weeks of treatment, blood glucose, coagulation markers, pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), and anti-inflammatory cytokines (IL-35, TGF-β1, IL-10) were analyzed. Histopathological examination of the liver, kidney, pancreas, and spleen was conducted. Immunohistochemistry was used to assess hepatic NF-κB expression.STZ significantly elevated pro-inflammatory cytokines (IL-1β, TNF-α, IL-6) and anti-inflammatory cytokines (IL-35, TGF-β1, IL-10), along with increased hepatic NF-κB expression and histopathological abnormalities in immune organs. NRX significantly reduced inflammatory cytokines, improved histopathological changes in organs, and decreased hepatic NF-κB expression. The combination therapy (NRX + SITA) achieved superior immune modulation, with enhanced cytokine profile restoration, reduced hepatic NF-κB expression, and near-complete histopathological normalization.This study underscores the promise of combining nanoparticle-based drug delivery with established therapies like sitagliptin to achieve superior immune modulation and inflammation control, presenting a potential therapeutic strategy for managing diabetes complications.
The Role of Th17/Treg Axis in Retinal Pathology Associated with Diabetes and Treatment OptionsMickael, Kubick, Miftari
et alBiology (Basel) (2025) 14 (3)
Abstract: Diabetic retinopathy (DR) is a major complication of diabetes, leading to vision impairment and blindness. The pathogenesis of DR involves multiple factors, including hyperglycemia-induced vascular damage, hypertension, obesity, anemia, immune dysregulation, and disruption of the blood-retinal barrier (BRB). Th17 and Treg cells, two types of CD4+ T cells, play opposing roles in inflammation. Th17 cells are pro-inflammatory, producing cytokines such as IL-17A, while Treg cells help suppress immune responses and promote anti-inflammatory effects. Recent studies highlight the importance of the Th17/Treg balance in retinal inflammation and disease progression in DR. Our literature review reveals an imbalance in DR, with increased Th17 activity and reduced Treg function. This shift creates a pro-inflammatory environment in the retina, worsening vascular leakage, neovascularization, and vision loss. The limited infiltration of Treg cells suggests that Th17 cells may uniquely infiltrate the retina by overwhelming or outnumbering Tregs or increasing the expression of recruiting chemokines, rather than only taking advantage of a damaged BRB. Therapeutic strategies, such as neutralizing IL-17A and enhancing Treg function with compounds like IL-35 or curcumin, may reduce inflammation and retinal damage. Restoring the balance between Th17 and Treg cells could provide new approaches for treating DR by controlling inflammation and preventing further retinal damage.
Increased Peripheral Interleukin-35 Suppresses CD4+ T and CD8+ T-Cell Activity in Patients Living with Chronic Human Immunodeficiency Virus-1 InfectionLi, Tong, Chen
et alViral Immunol (2025)
Abstract: Interleukin-35 (IL-35) has an immunosuppressive function through the regulation of immune cells during infectious diseases, autoimmune disorders, and cancers. The modulatory role of IL-35 in T lymphocytes, which are involved in host immune responses during human immunodeficiency virus-1 (HIV-1) infection, has not been elucidated. The aim of the current study was to investigate the role of regulatory function of IL-35 to T-cell activity in patients living with chronic HIV-1 infection. Sixty-seven patients living with chronic HIV-1 infection and 17 controls were enrolled in the study. IL-35 levels were measured via an enzyme-linked immunosorbent assay. Purified CD4+ and CD8+ T cells were stimulated with recombinant human IL-35. The secretion of cytokines and cytotoxic molecules, the mRNA levels of IL-35 receptor subunits and transcription factors, the expression of immune checkpoint molecules, and cell proliferation were assessed to evaluate the effect of IL-35 on T lymphocyte function in vitro. Compared with controls, patients living with chronic HIV-1 infection presented increased plasma IL-35 levels. IL-35 stimulation did not affect either the expression of IL-35 receptor subunits or the proliferation of CD4+ and CD8+ T cells from either patients living with chronic HIV-1 infection or controls. IL-35 stimulation downregulated transcription factor mRNA expression and cytokine secretion by CD4+ T cells as well as cytotoxic molecule production by CD8+ T cells from both patients living with chronic HIV-1 infection and controls. This process was accompanied by increased expression of immune checkpoint molecules on CD4+ and CD8+ T cells. The addition of IL-35 also reduced perforin and granzyme B secretion by HIV-1-specific CD8+ T cells from patients living with chronic HIV-1 infection. Increased plasma IL-35 in patients living with chronic HIV-1 infection might dampen the activation of CD4+ and CD8+ T cells, leading to T-cell exhaustion.
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