In:
The Journal of Immunology, The American Association of Immunologists, Vol. 204, No. 4 ( 2020-02-15), p. 967-979
Abstract:
The inflammatory effects of IL-1α/β 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-1α. Furthermore, blocking IL-1α 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-1α to immediately counteract its inflammatory effects.
Type of Medium:
Online Resource
ISSN:
0022-1767
,
1550-6606
DOI:
10.4049/jimmunol.1901074
Language:
English
Publisher:
The American Association of Immunologists
Publication Date:
2020
detail.hit.zdb_id:
1475085-5
