IL-17A is a critical pro-inflammatory cytokine in autoimmune diseases such as psoriasis. Targeting of IL-17A is an effective strategy to treat patients with autoimmune diseases; however, relevant small molecule therapeutics have not yet been developed. Here, the small molecule drug fenofibrate was validated as an inhibitor of IL-17A through ELISA and surface plasmon resonance (SPR) assays. We further confirmed that fenofibrate blocked IL-17A signalings including the mitogen-activated protein kinase (MAPK) and NF-κB signaling pathways, in IL-17A-treated HaCaT cells, HEKa (human primary epidermal keratinocytes) and imiquimod (IMQ)-induced psoriasis mouse model. Fenofibrate attenuated systemic inflammation by suppressing Th17 populations and inflammatory cytokines, such as IL-1β, IL-6, IL-17A, and tumor necrosis factor (TNF). Surprisingly, fenofibrate upregulated LC3 and p62 in the psoriatic mouse group. The autophagy changes were caused by ULK1 pathway in hIL-17A-treated HaCaT and HEKa. In addition, the enhancement of autophagy by fenofibrate exerted anti-inflammatory effects, as demonstrated by the suppression of IL-6 and IL-8 in the IL-17A-treated keratinocytes. Thus, IL-17A-targeting fenofibrate can be a potential therapeutic for psoriasis and other autoimmune diseases via regulating autophagy.
Keywords: Anti-IL-17A small molecule inhibitor; Autoimmune diseases; Autophagy; Fenofibrate; Inflammation; Psoriasis.
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