IL-35 Decelerates the Inflammatory Process by Regulating Inflammatory Cytokine Secretion and M1/M2 Macrophage Ratio in Psoriasis

Abstract

IL-35 downregulates Th17 cell development and suppresses certain types of autoimmune inflammation such as collagen-induced arthritis and experimental autoimmune uveitis. Psoriasis is thought to be initiated by abnormal interactions between cutaneous keratinocytes and systemic immune cells. However, the role of IL-35 in psoriasis remains unclear. In this study, we assessed IL-35 in three well-known psoriasis models: a human keratinocyte cell line (HaCaT), a keratin 14 (K14)-vascular endothelial growth factor A (VEGF-A)-transgenic (Tg) mouse model, and an imiquimod-induced psoriasis mouse model. First, we found that IL-35 suppressed the expression of IL-6, CXCL8, and S100A7, which are highly upregulated by a mixture of five proinflammatory cytokines in HaCaT. Second, a plasmid coding for the human IL-35 sequence coated with cationic liposomes showed potent immunosuppressive effects on K14-VEGF-A-Tg and imiquimod-induced psoriasis mouse models. In the K14-VEGF-A-Tg model, our results showed that several types of proinflammatory cytokines were significantly reduced, whereas IL-10 was remarkably induced by IL-35. Compared with pcDNA3.1, there was a small number of CD4(+)IL-17(+) T cells and a large number of CD4(+)IL-10(+) and CD4(+)CD25(+)Foxp3(+) T cells in the IL-35 group. Most importantly, we found that IL-35 decreased the total number of macrophages and ratio of M1/M2 macrophages, which has not been reported previously. In addition, compared with dexamethasone, IL-35 showed long-term therapeutic efficacy. In summary, our results strongly indicate that IL-35 plays a potent immunosuppressive role in psoriasis. Thus, IL-35 has potential for development as a new therapeutic strategy for patients with chronic psoriasis and other cutaneous inflammatory diseases.

IL‐35 ameliorates collagen‐induced arthritis by promoting TNF‐α‐induced apoptosis of synovial fibroblasts and stimulating M2 macrophages polarization

“…Similarly, Zhang et al . previously reported that the total amount of macrophages and the ratio of M1/M2 polarization were decreased by the IL‐35 in mice psoriasis models.…”

Clinical significance of weak interleukin‐35 expression in patients with psoriasis

“…In contrast, in the keratin 14–VEGF–A‐transgenic mouse model, IL‐35 has different functions in regulating innate or adaptive immune reactions. For example, the IL‐10 concentrations or the number of CD4+CD10+ or CD4+CD25+Foxp3+ T cells can be dramatically induced by IL‐35; however, this cytokine can decrease the total number of macrophages and lower the ratio of M1/M2 macrophages, which are dominant in the innate immunity . However, Pablo et al .…”

“…As Zhang et al . have reported, in a typical psoriasis model, namely the keratin 14 K14–vascular endothelial growth factor A–transgenic mouse model, expression of IL‐10 and counts of CD4+CD10+ or CD4+CD25+Foxp3+ T cells in the peripheral blood increase markedly after treatment with IL‐35, indicating that IL‐35 plays a critical role in dysregulation of the immune system in pathogenesis of psoriasis .…”

Interleukin‐35 in immune‐related diseases: protection or destruction

“…Recent results suggest that the plasma concentration of IL‐35 is lower in psoriasis patients than in healthy individuals . Furthermore, it was found that IL‐35 could alleviate the pathological characteristics of severe psoriatic lesions in K14‐VEGF‐A transgenic mice by reducing the ratio of the total number of macrophages to M1/M2 macrophages …”

“…47 lesions in K14-VEGF-A transgenic mice by reducing the ratio of the total number of macrophages to M1/M2 macrophages. 48,49…”