IL-12 regulates type 3 immunity through interfollicular keratinocytes in psoriasiform inflammation.

Autor:	Zwicky P; Institute of Experimental Immunology, University of Zurich, 8057 Zurich, Switzerland., Ingelfinger F; Institute of Experimental Immunology, University of Zurich, 8057 Zurich, Switzerland., Silva de Melo BM; Institute of Experimental Immunology, University of Zurich, 8057 Zurich, Switzerland.; Center for Research in Inflammatory Diseases, Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirão Preto Sao Paulo, Brazil., Ruchti F; Institute of Experimental Immunology, University of Zurich, 8057 Zurich, Switzerland.; Section of Immunology, Vetsuisse Faculty, University of Zurich, 8057 Zurich, Switzerland., Schärli S; Institute of Experimental Immunology, University of Zurich, 8057 Zurich, Switzerland., Puertas N; Institute of Experimental Immunology, University of Zurich, 8057 Zurich, Switzerland., Lutz M; Institute of Experimental Immunology, University of Zurich, 8057 Zurich, Switzerland., Phan TS; Department of Dermatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland., Kündig TM; Department of Dermatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland., Levesque MP; Department of Dermatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland., Maul JT; Department of Dermatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland., Schlapbach C; Department of Dermatology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland., LeibundGut-Landmann S; Institute of Experimental Immunology, University of Zurich, 8057 Zurich, Switzerland.; Section of Immunology, Vetsuisse Faculty, University of Zurich, 8057 Zurich, Switzerland., Mundt S; Institute of Experimental Immunology, University of Zurich, 8057 Zurich, Switzerland., Becher B; Institute of Experimental Immunology, University of Zurich, 8057 Zurich, Switzerland.
Jazyk:	angličtina
Zdroj:	Science immunology [Sci Immunol] 2021 Oct 22; Vol. 6 (64), pp. eabg9012. Date of Electronic Publication: 2021 Oct 22.
DOI:	10.1126/sciimmunol.abg9012
Abstrakt:	Psoriasis is a chronic inflammatory skin disorder underpinned by dysregulated cytokine signaling. Drugs neutralizing the common p40 subunit of interleukin-12 (IL-12) and IL-23 represented a therapeutic breakthrough; however, new drugs that block the IL-23p19 subunit and spare IL-12 are more effective, suggesting a regulatory function of IL-12. To pinpoint the cell type and underlying mechanism of IL-12–mediated immune regulation in psoriasis, we generated a conditional Il12rb2 -knockout (KO)/reporter mouse strain. We detected Il12rb2 expression in T cells and a specific subset of interfollicular (IF) keratinocytes. Analysis of single-cell RNA-sequencing (scRNAseq) data from patients with psoriasis confirmed a similar expression pattern in the human skin. Deletion of Il12rb2 across the hematopoietic compartment did not alter the development of Aldara-induced psoriasiform inflammation. However, depletion of Il12rb2 in keratinocytes exacerbated disease development, phenocopying the Il12rb2 germline knockout. Protective IL-12 signaling blocked the hyperproliferation of keratinocytes, maintained skin barrier integrity, and diminished disease-driving IL-23/type 3 immune circuits. In line, specific IL-23p19 blockade led to a more profound reduction of psoriatic keratinocyte expression signatures in the skin of patients with psoriasis than combined IL-12/IL-23 inhibition. Collectively, we provide a potential explanation for the superior efficacy of IL-23p19 inhibitors in psoriasis and describe an unperceived role of IL-12 in maintaining skin epithelial cell homeostasis.
Databáze:	MEDLINE
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