IL36RN Human

Interleukin-36 Receptor Antagonist (IL-36RA), also known as IL-1F5, is a member of the IL-1 family of cytokines. This protein plays a crucial role in modulating inflammatory responses and is involved in innate immunity and anti-inflammatory processes .

IL-36RA is a secreted protein that antagonizes the proinflammatory signals of the IL-36 family members, which include IL-36α, IL-36β, and IL-36γ . The IL-36 family belongs to the larger IL-1 superfamily and consists of three agonists (IL-36α/β/γ), one antagonist (IL-36RA), one cognate receptor (IL-36R), and one accessory protein (IL-1RAcP) . The receptor activation follows a two-step mechanism where the agonist first binds to IL-36R, and the resulting binary complex recruits IL-1RAcP. This assembled ternary complex brings together intracellular TIR domains of receptors, which activate downstream NF-κB and MAPK signaling .

IL-36RA is normally expressed at low levels but is induced upon stimulation. It acts on various cells, including epithelial and immune cells . In the skin, IL-36RA contributes to host defense through inflammatory responses. However, when dysregulated, IL-36RA stimulates keratinocytes and immune cells to enhance the Th17/Th23 axis, leading to psoriatic-like skin disorders . Genetic mutations in IL-36RA are associated with generalized pustular psoriasis, a rare but life-threatening skin disease .

Deficiency of IL-36RA (DITRA) is a life-threatening autoinflammatory disease caused by autosomal-recessive mutations in the IL36RN gene . Patients with DITRA develop recurrent episodes of generalized pustular psoriasis (GPP) with systemic inflammation and fever . Biological treatments targeting inflammatory cytokines, such as TNF-alpha, IL-12/23, and IL-17, have shown varying degrees of efficacy in treating DITRA .

Anti-IL-36 antibodies have been shown to attenuate IMQ or IL-23 induced skin inflammation in mice, illustrating IL-36’s involvement in mouse models of psoriasis . Further research and clinical trials are warranted to explore the therapeutic potential of IL-36RA in treating inflammatory and autoimmune diseases.