IL-36 Receptor Antagonist Deficiency Linked to Reduced Skin Chemokine and Heightened Psoriatic Inflammation
Researchers using mouse models and human patient data have found that deficiency of the IL-36 receptor antagonist (DITRA) reduces expression of the chemokine CCL27 in skin, disrupting immune homeostasis before disease onset. This disruption is accompanied by overgrowth of the skin bacterium Cutibacterium acnes, and restoring CCL27 levels experimentally reduced inflammation severity. The findings suggest a novel mechanism explaining why DITRA patients are predisposed to severe generalized pustular psoriasis (GPP).
DITRA is a rare autoinflammatory disorder caused by loss-of-function mutations in the IL36RN gene, which leads to unchecked IL-36 cytokine signaling and severe recurrent episodes of Generalized Pustular Psoriasis (GPP). Using IL-36Ra-deficient mice (Il36rn-/-) that mimic the human condition, researchers found that even before visible disease onset, the skin shows disrupted immune homeostasis characterized by significantly reduced expression of the chemokine CCL27. This homeostatic disruption was associated with dysbiosis of the skin microbiome, specifically an outgrowth of Cutibacterium acnes. Critically, intradermal injection of recombinant CCL27 prior to disease induction substantially reduced the severity of psoriasiform inflammation in the mouse model, pointing to a protective role for this chemokine. Transcriptomic analysis of GPP patient skin corroborated these findings, showing decreased CCL27 expression in both lesional and non-lesional skin compared to healthy controls. Together, the results propose that CCL27 deficiency is a pre-disease vulnerability factor in DITRA, offering a potential new therapeutic target alongside existing anti-IL-36R monoclonal antibody treatments.
What's missing
The study does not address whether restoring CCL27 in human DITRA patients is clinically feasible or safe, nor does it clarify the causal direction between CCL27 reduction and Cutibacterium acnes dysbiosis. The mouse model, while recapitulating key features of DITRA, may not fully replicate human skin immunology, and the patient transcriptomic cohort size is not specified, limiting generalizability.
What different sources said
- bioRxivCenter
Deficiency of IL-36 receptor antagonist (DITRA) is associated with decreased homoeostatic CCL27 expression leading to heightened dermal inflammation.
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