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

Elaina Melton, Hongyu Qiu, Elaina Melton, Hongyu Qiu

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.

Keywords: IL-1 receptor family; IL-36; IL-36R; IL-38; inflammation; tissue fibrosis.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Structural and molecular depiction of interleukin 36 receptor (IL-36R) signaling cascade. Upon binding to its agonists (IL-36α, IL-36β, or IL-36γ), IL-36R heterdimerizes with its co-receptor IL-1R3 (IL-1RAcP). The formation of the IL-36R/IL-36/IL-1R3 complex results in the recruitment of MyD88 and IRAKs, which subsequently activates the MAPK and NFKB pathways. Activation of MAPK results in the transcription of inflammatory genes regulated by AP-1, while the phosphorylation of IKβα (a negative regulator of NFKB) by Ikβ kinase leads to the translocation of NFKB to the nucleus, which aids in the transcription of genes important for mediating inflammation. The IL-36R mediated activation of pro-inflammatory gene expression can be inhibited by IL-36Ra or IL-38. Extracellular domain (ECD), toll/interleukin-1 receptor domain (TIR), myeloid differentiation primary response 88 (MyD88), interleukin-1 receptor associated kinases like 1 and 2 (IRAKs), mitogen-activated protein kinase (MAPK), activator protein-1 (AP-1), NF-Kappa-B Inhibitor Alpha (IKβα), and nuclear factor kappa light chain enhancer of activated B cells (NFKB), CCl, C-C motif chemokine ligand; CXCL, C-X-C motif chemokine ligand; IFN, interferon.
Figure 2
Figure 2
Major contributions of immune and non-immune cells in tissue fibrosis. During fibrosis, macrophages and T cells promote fibrosis via activation of myofibroblasts and release of pro-fibrotic inflammatory factors. Non-immune cells can also be transformed into “myofibroblast-like” cells to produce collagen factors that advance the progression of fibrosis. TGF, transforming growth factor; PDGF, platelet-derived growth factor; EMT, epithelial to mesenchymal transformation: EndMT, endothelial to mesenchymal transformation; ECM, extracellular matrix; TSLP, thymic stromal lymphopoietin; Endothelin-1 (ET).
Figure 3
Figure 3
Potential molecular mechanisms of IL-36R induced tissue fibrosis. IL-36R signaling promotes fibrosis development in tissues by (1) regulating dendritic cell and T cell immune responses through a MyD88 dependent pathway and (2) driving inflammation, extracellular matrix (ECM), and fibrogenic gene upregulation in fibroblasts. Nod-like receptor family pyrin domain containing 3 (NLRP3).

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