Intracellular Il-1 Receptor Antagonist Isoform 1 Released From Keratinocytes Upon Cell Death Acts As An Inhibitor For The Alarmin Il-1 Alpha

The inflammatory effects of IL-1 alpha/beta are controlled by IL-1R antagonist (IL-1Ra). One IL-1Ra isoform is secreted, whereas three other isoforms (intracellular IL-1Ra [icIL-1Ra] 1, 2, and 3) are supposed to remain intracellular because of the absence of a signal peptide. In contrast to the well-characterized function of the secreted isoform, the biological role of the intracellular isoforms remains largely unclear. icIL-1Ra1 represents the major isoform in keratinocytes. We created icIL-1Ra1(-/-) mice and investigated the role of icIL-1Ra1 in Aldara (5% imiquimod)-induced psoriasis-like skin inflammation. Naive icIL-1Ra1(-/-) mice bred habitually and exhibited a normal phenotype. icIL-1Ra1 deficiency aggravated Aldara-induced skin inflammation, as demonstrated by increased ear thickness and increased mRNA levels of key proinflammatory cytokines. No intracellular effect of icIL-1Ra1 could be detected in isolated keratinocytes using RNA-sequencing analysis; however, Aldara treatment led to caspase 1/11-, caspase 8-, and RIPK3-independent keratinocyte cell death accompanied by the release of both icIL-1Ra1 and IL-1 alpha. Furthermore, blocking IL-1 alpha attenuated the clinical severity of Aldara-induced ear thickening in icIL-1Ra1(-/-) mice. Our data suggest that upon keratinocyte damage icIL-1Ra1 acts extracellularly as an antagonist of the alarmin IL-1 alpha to immediately counteract its inflammatory effects.