Immunity to commensal skin fungi promotes psoriasiform skin inflammation
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ABSTRACT:
PROVIDER: PRJNA605153 | ENA |
REPOSITORIES: ENA
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Project description:Psoriasis is a chronic inflammatory skin disorder underpinned by dysregulated cytokine signaling. Drugs neutralizing the common p40 subunit of 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. In order 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 scRNAseq data from psoriasis patients confirmed this expression pattern in the human skin. Mechanistically, deletion of Il12rb2 in the keratinocyte compartment led to exacerbated psoriasiform inflammation. Protective IL-12 signaling blocked the hyperproliferation of keratinocytes, maintained skin barrier integrity, and, importantly, diminished disease-driving IL-23/type 3 immune circuits. 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.
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Project description:IL-6 inhibition has been unsuccessful in treating psoriasis, despite high levels of tissue and serum IL-6 in patients. Additionally, de novo psoriasis onset has been reported following IL-6 blockade in rheumatoid arthritis patients. To explore mechanisms underlying these clinical observations, we backcrossed an established psoriasiform mouse model (IL-17C+ mice) with IL-6 deficient mice (IL-17C+KO) and examined the cutaneous phenotype. IL-17C+KO mice initially exhibited decreased skin inflammation, however this decrease was transient and reversed rapidly, concomitant with increases in skin Tnf, Il36α/β/γ, Il24, epigen and S100a8/a9 to levels higher than those found in IL-17C+ mice. Comparison of IL-17C+ and IL-17C+KO mouse skin transcriptomes with that of human psoriasis skin, revealed significant correlation among transcripts of psoriasis patient skin and IL-17C+KO mouse skin, and confirmed an exacerbation of the inflammatory signature in IL-17C+KO mice that aligns closely with human psoriasis. Transcriptional analyses of IL-17C+ and IL-17C+KO primary keratinocytes confirmed increased expression of proinflammatory molecules, suggesting that in the absence of IL-6, keratinocytes increase production of numerous additional proinflammatory cytokines. These preclinical findings may provide insight into why arthritis patients being treated with IL-6 inhibitors develop new onset psoriasis and why IL-6 blockade for the treatment of psoriasis has not been clinically effective.
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Project description:miR-146a acts as a negative feedback regulator of inflammation. To investigate the role of miR-146a in psoriasis psoriasiform skin inflammation was indeuced in Mir-146a-/- and wild type mice (C57BL6J) by topical applciation of imiquimod (IMQ)-cream (Aldara). Gene expression profiling (Affymetrix) was used to identify transcriptomic changes associated with psoriasis-like skin inflammation in wild type vs. miR-146a -/-mice. A daily topical dose of 31.25 mg of Aldara cream (5% IMQ) was applied on the right ear of miR-146a -/- and C57BL/6 mice on three consecutive days to induce psorisis-like skin inflammation. Mice were sacrificed at day 4. Ear flaps were collected for total RNA extraction and hybridization on Affymatrix GeneTitan plate format Gene ST 2.1 (mouse).
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