Journal
JOURNAL OF INVESTIGATIVE DERMATOLOGY
Volume 139, Issue 6, Pages 1306-1317Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jid.2018.11.031
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Funding
- Fondation pour la Recherche Medicale [DMP20101120387]
- Fondation ARC pour la Recherche sur le Cancer [PGA1RF201702053889]
- INSERM
- University of Nice-Sophia-Antipolis
- Clinical Research Hospital Program (PHRC 2011) from the French Ministry of Health
- French Government (National Research Agency) through the Investments for the Future LABEX SIGNALIFE [ANR-11-LABX-0028-01]
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Inflammatory caspases, activated within the inflammasome, are responsible for the maturation and secretion of IL-1 beta/IL-18. Although their expression in psoriasis was shown several years ago, little is known about the role of inflammatory caspases in the context of psoriasis. Here, we confirmed that caspases 1, 4, and 5 are activated in lesional skin from psoriasis patients. We showed in three psoriasis-like models that inflammatory caspases are activated, and accordingly, caspase 1/1 beta invalidation or pharmacological inhibition by Ac-YVAD-CMK (i.e., Ac-Tyr-Val-Ala-Asp-chloromethylketone) injection induced a decrease in ear thickness, erythema, scaling, inflammatory cytokine expression, and immune cell infiltration in mice. We observed that keratinocytes were primed to secrete IL-1 beta when cultured in conditions mimicking psoriasis. Generation of chimeric mice by bone marrow transplantation was carried out to decipher the respective contribution of keratinocytes and/or immune cells in the activation of inflammatory caspases during psoriasis-like inflammatory response. Our data showed that the presence of caspase 1/11 in the immune system is sufficient for a fully inflammatory response, whereas the absence of caspase 1/11 in keratinocytes/fibroblasts had no impact. In summary, our study indicates that inflammatory caspases activated in immune cells are implicated in psoriasis pathogenesis.
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