Il36rn

IL36RN is a protein-coding gene in Homo sapiens that encodes the interleukin-36 receptor antagonist (IL-36Ra), a member of the interleukin-1 cytokine family. The gene resides on chromosome 2 at position 2q11.2 and is expressed primarily in epithelial tissues, including skin, lungs, and the gastrointestinal tract. The IL-36Ra protein functions as an endogenous inhibitor of IL-36 signaling by competitively binding to the IL-36 receptor complex (IL-36R/IL-1RAcP) without triggering downstream signaling. This regulatory activity dampens innate immune responses and prevents excessive inflammation mediated by IL-36α, IL-36β, and IL-36γ.

Mutations in IL36RN have been implicated in a spectrum of autoinflammatory disorders, most notably generalized pustular psoriasis (GPP). Autosomal recessive loss‑of‑function variants result in heightened IL-36 activity and skin hyperplasia. Other associations include pyoderma gangrenosum and annular erythema, where impaired IL-36Ra leads to chronic neutrophilic dermatoses. The disease phenotype demonstrates incomplete penetrance and variable expressivity, underscoring the influence of additional genetic and environmental modifiers.

The IL-36Ra protein comprises 152 amino acids and contains a signal peptide that directs secretion. Structural analyses reveal a globular domain with cysteine residues critical for maintaining disulfide bonds, essential for receptor binding affinity. Functional assays demonstrate that recombinant IL-36Ra can reverse IL-36-induced chemokine production in keratinocytes and dermal fibroblasts.

In mouse models, targeted deletion of Il36rn produces spontaneous psoriasis‑like skin inflammation, recapitulating key aspects of the human condition such as pustule formation and exaggerated cytokine release. These models validate IL-36Ra as a central modulator of cutaneous innate immunity and as a therapeutic target.

Screening for IL36RN variants is increasingly incorporated into diagnostic panels for severe psoriatic disease, informing prognosis and guiding biologic therapy choices that selectively block IL-36 pathways.