| First Author | Martin P | Year | 2020 |
| Journal | J Immunol | Volume | 204 |
| Issue | 4 | Pages | 967-979 |
| PubMed ID | 31932497 | Mgi Jnum | J:284108 |
| Mgi Id | MGI:6388950 | Doi | 10.4049/jimmunol.1901074 |
| Citation | Martin P, et al. (2020) Intracellular IL-1 Receptor Antagonist Isoform 1 Released from Keratinocytes upon Cell Death Acts as an Inhibitor for the Alarmin IL-1alpha. J Immunol 204(4):967-979 |
| abstractText | The inflammatory effects of IL-1alpha/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-1alpha. Furthermore, blocking IL-1alpha 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-1alpha to immediately counteract its inflammatory effects. |
