IL-1 Family Cytokines in Inflammatory Dermatoses: Pathogenetic Role and Potential Therapeutic Implications

Abstract

The interleukin-1 (IL-1) family is involved in the correct functioning and regulation of the innate immune system, linking innate and adaptative immune responses. This complex family is composed by several cytokines, receptors, and co-receptors, all working in a balanced way to maintain homeostasis. Dysregulation of these processes results in tissue inflammation and is involved in the pathogenesis of common inflammatory dermatoses such as psoriasis, hidradenitis suppurativa, and atopic dermatitis. Therefore, therapeutic targeting of IL-1 pathways has been studied, and several monoclonal antibodies are currently being assessed in clinical trials. So far, promising results have been obtained with anti-IL-36R spesolimab and imsidolimab in pustular psoriasis, and their efficacy is being tested in other conditions.

Keywords: IL-1; IL-33; IL-36; IL-36R; atopic dermatitis; bermekimab; etokimab; hidradenitis suppurativa; imsidolimab; pathogenesis; psoriasis; pustular psoriasis; spesolimab.

Figure 1

Signaling pathways and regulatory mechanisms involved in the IL-1 family. (A). Upon binding of IL-1α and IL-β to their receptor IL-1R1 altogether with co-receptor IL-1RAcP, induction of signal transduction with recruitment of myeloid differentiation primary response 88 (MyD88) accessory protein and IL-1R associated kinase (IRAK) proteins, ultimately ending in the activation of the transcription factor nuclear factor κB (NF- κB) and the transcription of proinflammatory genes. Regulatory mechanisms include IL-1R2 and IL-1Ra: IL-1R2 can exist as a soluble receptor or membrane bound, acting as a decoy receptor as it is unable to recruit the co-receptor to induce signal transduction. Finally, IL-1Ra acts as a competitive inhibitor by binding to IL-1R1. (B). Likewise, IL-33 binds to the receptor ST2, inducing the recruitment of co-receptor IL-1RAcP and resulting in signal transduction into the nucleus with transcription of proinflammatory genes. In this family, the soluble form of ST2 also acts as a decoy receptor. IL-18 binds to IL-18Rα and recruits the co-receptor IL-18Rβ resulting in pro-inflammatory signaling. IL-18 binds to the soluble protein IL-18BP preventing binding to the receptor. IL-37 is an anti-inflammatory cytokine and upon binding to IL-18Rα induces recruitment of the Single Ig and TIR Domain Containing (SIGIRR or IL-1R8), ultimately producing inhibitory signaling. (C). IL-36 cytokines also induce pro-inflammatory gene transcription by binding to the receptor IL-36R and recruiting co-receptor IL-1RAcP. IL-36Ra is the competitive antagonist of IL-36 cytokines. The anti-inflammatory cytokine IL-38 forms a complex with IL-36R and three immunoglobulin domain-containing IL-1 receptor-related 2 (TIGIRR-2 or IL1RAPL1), also inducing inhibitory signaling to regulate the pro-inflammatory gene activation.