IL-36 Cytokines in Psoriasis and Inflammatory Skin Diseases

IL-36 cytokines are key drivers of skin inflammation, and neutralizing antibodies targeting IL-36R have potential for patients with generalized pustular psoriasis (GPP) particularly those with more severe disease. It is also possible that IL-36 plays a role in inflammatory skin diseases besides psoriasis, according to highlights from a review article published in Cytokine.

The family of cytokines, IL-36, includes a receptor antagonist (IL-36Ra) and 3 pro-inflammatory agonists (IL-36α, IL-36β, and IL-36γ) which researchers say bind and signal through IL-36R and the IL-1R accessory protein (IL-1RAcP), causing unpredictable functional consequences. Dysregulated IL-36 pathway activation has been linked to inflammatory skin conditions. By review, researchers sought to highlight the cellular source of IL-36 cytokines, their effects as they signal across cells, and their association to psoriasis, atopic and allergic contact dermatitis, and acne inversa.

TNFα, IL-17, and IL-22 (psoriasis-associated cytokines) alone or in combination cause IL-36 expression. Some of their activity is facilitated by a transcriptional coactivator (IκBζ). IL36 gene expression by keratinocytes is induced or enhanced by IL-36 cytokines. The IL36 gene expression is also found in monocytes and macrophages, and in murine bone marrow-derived dendritic cells and CD4+ T cells. Upregulated expression of IL-36 cytokines have been found in psoriatic skin lesions.

Researchers noted that the binding to IL-36 by IL-36Ra blocks agonist binding, preventing IL-1RAcP recruitment and downstream signaling. Immune cell infiltration into the skin may be engendered by IL-36 acting on endothelial cells directly and indirectly. Studies with mice have shown inflammatory IL-36 effects could be mitigated with IL-36R blocking antibody. Numerous in vitro studies have shown the self-amplifying loop and feedback between key psoriasis cytokines and IL-36. And human keratinocytes stimulated with IL-36 agonists demonstrate upregulation of genes associated with psoriatic skin.

Researchers said, “Given the strong human genetics linking GPP to over-activation of the IL-36 pathway, there is great potential for novel therapies that inhibit this pathway to be of therapeutic benefit to patients.” The occurrence of IL36RN mutations in deficiency of interleukin 36-receptor antagonist forms of GPP demonstrated to the investigators that IL-36 cytokines are key drivers of skin inflammation.

Disclosure: This research was supported by Janssen Research and Development. Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.

Reference

Sachen KL, Arnold Greving CN, Towne JE. Role of IL-36 cytokines in psoriasis and other inflammatory skin conditions. Cytokine. August, 2022;156:155897. doi:10.1016/j.cyto.2022.155897