Interleukin-36 Cytokine/Receptor Signaling: A New Target for Tissue Fibrosis

Abstract

Tissue fibrosis is a major unresolved medical problem, which impairs the function of various systems. The molecular mechanisms involved are poorly understood, which hinders the development of effective therapeutic strategies. Emerging evidence from recent studies indicates that interleukin 36 (IL-36) and the corresponding receptor (IL-36R), a newly-characterized cytokine/receptor signaling complex involved in immune-inflammation, play an important role in the pathogenesis of fibrosis in multiple tissues. This review focuses on recent experimental findings, which implicate IL-36R and its associated cytokines in different forms of organ fibrosis. Specifically, it outlines the molecular basis and biological function of IL-36R in normal cells and sums up the pathological role in the development of fibrosis in the lung, kidney, heart, intestine, and pancreas. We also summarize the new progress in the IL-36/IL-36R-related mechanisms involved in tissue fibrosis and enclose the potential of IL-36R inhibition as a therapeutic strategy to combat pro-fibrotic pathologies. Given its high association with disease, gaining new insight into the immuno-mechanisms that contribute to tissue fibrosis could have a significant impact on human health.

Therapeutic Targeting of Intestinal Fibrosis in Crohn’s Disease

“…Endogenous agonists act as proinflammatory cytokines and the IL-36 signaling also promotes secretion of pro-fibrotic mediators. Thus, a potential role of IL-36R inhibition as a therapeutic strategy to treat pro-fibrotic disorders has been proposed [120]. Antibodies against IL-36R were investigated in DSS or TNBS-induced mice colitis and showed to significantly reduce established fibrosis [121].…”

Current Perspectives on Nucleus Pulposus Fibrosis in Disc Degeneration and Repair

“…IL-1β was shown to stimulate the expression of collagen I and III in human NP cells, suggesting a fibroblastic phenotype [ 60 ]. IL-36 is a group of cytokines in the IL-1 family and fosters the secretion of profibrotic regulators, leading to fibrosis in the lungs, kidneys, heart, intestines and pancreas [ 99 ]. The specific role of IL-36 in NP fibrosis or IDD has never been studied.…”

Psoriasis: Recent progress in molecular‐targeted therapies

“…The Toll/interleukine-1 resistance (TIR) domain recruits the adaptor protein MyD88, which interacts with the signaling molecules associated with downward pathways, such as NF-κB and MAP kinase via the activation of the interleukin-1 receptor associated kinases (IRAKs). 138,194 Spesolimab is a humanized monoclonal antibody against IL-36 receptor. 143 In a phase 1 proof-of-concept study on seven GPP cases, a single intravenous administration of spesolimab (10 mg/kg) significantly reduced the GPP severity score and maintained the status up to week 20. based on the biochemical functions and homologies.…”

“…The extracellular region of the receptor consists of three Ig‐like domains necessary for the ligand‐specific binding. The Toll/interleukine‐1 resistance (TIR) domain recruits the adaptor protein MyD88, which interacts with the signaling molecules associated with downward pathways, such as NF‐κB and MAP kinase via the activation of the interleukin‐1 receptor associated kinases (IRAKs) 138,194 . IL‐36a works as a physiological competitive inhibitor against IL‐36‐signaling…”