Caspase 1/11 Deficiency or Pharmacological Inhibition Mitigates Psoriasis-Like Phenotype in Mice

• Published in: Journal of investigative dermatology Vol. 139; no. 6; pp. 1306 - 1317
• Main Authors: Aira, Lazaro Emilio, Gonçalves, Diogo, Bossowski, Jozef P., Rubio-Patiño, Camila, Chiche, Johanna, Paul-Bellon, Rachel, Mondragón, Laura, Gesson, Maéva, Lecucq-Ottavi, Priscillia, Obba, Sandrine, Colosetti, Pascal, Luciano, Frédéric, Bailly-Maitre, Béatrice, Boyer, Laurent, Jacquel, Arnaud, Robert, Guillaume, Ricci, Jean-Ehrland, Ortonne, Jean-Paul, Passeron, Thierry, Lacour, Jean-Philippe, Auberger, Patrick, Marchetti, Sandrine
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.06.2019; Nature Publishing Group
• Subjects: Amino Acid Chloromethyl Ketones - administration & dosage; Animals; Biopsy; Bone Marrow Transplantation; Caspase 1 - deficiency; Caspase 1 - genetics; Caspase 1 - immunology; Caspase Inhibitors - administration & dosage; Caspases, Initiator - deficiency; Caspases, Initiator - genetics; Caspases, Initiator - immunology; Caspases, Initiator - metabolism; Cells, Cultured; Clinical Trials as Topic; Female; Humans; Injections, Intraperitoneal; Interleukin-1beta - immunology; Interleukin-1beta - metabolism; Keratinocytes; Life Sciences; Male; Mice; Mice, Knockout; Primary Cell Culture; Psoriasis - drug therapy; Psoriasis - immunology; Psoriasis - pathology; Signal Transduction - drug effects; Signal Transduction - immunology; Skin - immunology; Skin - pathology; Transplantation Chimera; Ac-YVAD-CMK; dKO; IMQ; TNF; WT
• ISSN: 0022-202X; 1523-1747
• DOI: 10.1016/j.jid.2018.11.031

Inflammatory caspases, activated within the inflammasome, are responsible for the maturation and secretion of IL-1β/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 1/11 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-1β 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.