Department of Clinical Immunology and Rheumatology, Amsterdam Rheumatology & immunology Center (ARC), Amsterdam University Medical Centers, location Academic Medical Center, University of Amsterdam, the Netherlands; Department of Experimental Immunology, Infection and Immunity Institute, Amsterdam University Medical Centers, location AMC, University of Amsterdam, the Netherlands.
UCB Pharma, Slough, UK.
J Autoimmun. 2020 Jul;111:102435. doi: 10.1016/j.jaut.2020.102435. Epub 2020 Apr 29.
The delta isoform of phosphoinositide 3-kinase (PI3Kδ) regulates various lymphocyte functions. Considering the key pro-inflammatory role of IL-17A and IL-17F cytokines in psoriasis and spondyloarthritis (SpA), we investigated the potential of PI3Kδ blockade to suppress IL-17A, IL-17F and associated pro-inflammatory cytokines that could synergize with IL-17A and IL-17F. Using in vitro studies with primary human cells and ex vivo studies with inflamed target tissues, we assessed if seletalisib, a selective PI3Kδ inhibitor, suppresses cytokine production by T cells and innate-like lymphocytes, and if seletalisib modulates the inflammatory responses in stromal cell populations in psoriasis (human dermal fibroblasts (HDF)) and SpA (fibroblast-like synoviocytes (FLS)). In vitro, seletalisib inhibited the production of pro-inflammatory cytokines, including IL-17A and IL-17F, from peripheral blood mononuclear cells (PBMCs), T helper 17 (Th17) cells as well as γδ-T cells and mucosal-associated invariant T cells. This inhibition resulted in decreased inflammatory activation of HDF in co-culture systems. Seletalisib was also efficacious in inhibiting SpA PBMCs and synovial fluid mononuclear cells (SFMCs) from producing pro-inflammatory cytokines. Furthermore, supernatant derived from cultured seletalisib-treated Th17 cells showed reduced potency for activating inflammatory responses from cultured SpA FLS and decreased their osteogenic differentiation capacity. Finally, analysis of inflamed SpA synovial tissue biopsies revealed activation of the PI3K-Akt-mTOR pathway. We observed that ex vivo seletalisib treatment of inflamed synovial tissue reduced IL-17A and IL-17F expression. Collectively, inhibition of PI3Kδ reduces the production of pro-inflammatory cytokines from IL-17-producing adaptive and innate-like lymphocytes and thereby inhibits downstream inflammatory and tissue remodeling responses. PI3Kδ-targeting may therefore represent a novel therapeutic avenue for the treatment of IL-17-mediated chronic inflammatory diseases such as psoriasis and SpA.
磷酸肌醇 3-激酶（PI3K）的δ同工型调节各种淋巴细胞功能。考虑到白细胞介素-17A（IL-17A）和白细胞介素-17F 细胞因子在银屑病和脊柱关节炎（SpA）中的关键促炎作用，我们研究了 PI3Kδ 阻断抑制 IL-17A、IL-17F 和相关促炎细胞因子的潜力，这些细胞因子可以与 IL-17A 和 IL-17F 协同作用。通过体外研究原代人细胞和体内研究炎症靶组织，我们评估了选择性 PI3Kδ 抑制剂塞拉替尼是否抑制 T 细胞和先天样淋巴细胞产生细胞因子，以及塞拉替尼是否调节银屑病（人真皮成纤维细胞（HDF））和 SpA（成纤维细胞样滑膜细胞（FLS））中基质细胞群体的炎症反应。体外，塞拉替尼抑制外周血单核细胞（PBMCs）、辅助性 T 细胞 17（Th17）细胞以及 γδ-T 细胞和黏膜相关不变 T 细胞产生促炎细胞因子，包括白细胞介素-17A（IL-17A）和白细胞介素-17F（IL-17F）。这种抑制导致共培养系统中 HDF 的炎症激活减少。塞拉替尼对抑制 SpA PBMCs 和滑液单核细胞（SFMCs）产生促炎细胞因子也有效。此外，来自培养的塞拉替尼处理 Th17 细胞的上清液显示出降低激活培养的 SpA FLS 炎症反应的效力，并降低其成骨分化能力。最后，对炎症性 SpA 滑膜组织活检的分析显示 PI3K-Akt-mTOR 途径的激活。我们观察到，体外塞拉替尼处理炎症性滑膜组织减少了白细胞介素-17A（IL-17A）和白细胞介素-17F（IL-17F）的表达。总之，PI3Kδ 的抑制减少了 IL-17 产生的适应性和先天样淋巴细胞产生的促炎细胞因子的产生，并抑制了下游的炎症和组织重塑反应。因此，PI3Kδ 靶向治疗可能代表治疗银屑病和 SpA 等 IL-17 介导的慢性炎症性疾病的一种新的治疗途径。
