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Title

Intracellular IL-1 receptor antagonist isoform 1 released from keratinocytes upon cell death acts as an inhibitor for the alarmin IL-1α

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Published in The Journal of immunology. 2020, vol. 204, no. 4, 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.
Identifiers
PMID: 31932497
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Article (Published version) (4.7 MB) - document accessible for UNIGE members only Limited access to UNIGE
Structures
Research groups Biologie des cytokines de la famille de l'interleukine-1 (1022)
Mécanisme de l'inflammation articulaire (44)
Project
Swiss National Science Foundation: 310030_172674
Citation
(ISO format)
RODRIGUEZ MARTIN, Praxedis Sina et al. Intracellular IL-1 receptor antagonist isoform 1 released from keratinocytes upon cell death acts as an inhibitor for the alarmin IL-1α. In: Journal of Immunology, 2020, vol. 204, n° 4, p. 967-979. doi: 10.4049/jimmunol.1901074 https://archive-ouverte.unige.ch/unige:134890

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Deposited on : 2020-04-22

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