title: The Inflammatory Caspases-1 and -11 Mediate the Pathogenesis of Dermatitis in Sharpin-Deficient Mice.
abstract: Chronic proliferative dermatitis in mice (cpdm) is a spontaneous multiorgan inflammatory disorder with pathological hallmarks similar to atopic dermatitis and psoriasis in humans. Cpdm mice lack expression of SHANK-associated RH domain-interacting protein, an adaptor of the linear ubiquitin assembly complex, which acts in the NF-κB pathway to promote inflammation and protect from apoptosis and necroptosis. Although skin inflammation in cpdm mice is driven by TNF- and RIPK1-induced cell death, the contribution of initiating innate immunity sensors and additional inflammatory pathways remains poorly characterized. In this article, we show that inflammasome signaling, including the expression and activation of the inflammatory caspase-1 and -11 and IL-1 family cytokines, was highly upregulated in the skin of cpdm mice prior to overt disease onset. Genetic ablation of caspase-1 and -11 from cpdm mice significantly reduced skin inflammation and delayed disease onset, whereas systemic immunological disease persisted. Loss of Nlrp3 also attenuated skin disease, albeit more variably. Strikingly, induction of apoptosis and necroptosis effectors was sharply decreased in the absence of caspase-1 and -11. These results position the inflammasome as an important initiating signal in skin disease pathogenesis and provide novel insights about inflammasome and cell death effector cross-talk in the context of inflammatory diseases.
authors.affiliation: Department of Microbiology and Immunology, McGill University, Montreal, Quebec H3G 0B1, Canada;
authors.forename: Todd
authors.initials: T
authors.lastname: Douglas
authors.affiliation: Department of Medicine, McGill University, Montreal, Quebec H3G 0B1, Canada;
authors.forename: Claudia
authors.initials: C
authors.lastname: Champagne
authors.affiliation: Department of Medicine, McGill University, Montreal, Quebec H3G 0B1, Canada;
authors.forename: Alexandre
authors.initials: A
authors.lastname: Morizot
authors.affiliation: Comparative Medicine and Animal Resources Centre, McGill University, Montreal, Quebec H3G 1Y6, Canada; and.
authors.forename: Jean-Martin
authors.initials: JM
authors.lastname: Lapointe
authors.affiliation: Department of Microbiology and Immunology, McGill University, Montreal, Quebec H3G 0B1, Canada; Department of Medicine, McGill University, Montreal, Quebec H3G 0B1, Canada; Department of Biochemistry, McGill University, Montreal, Quebec H3G 0B1, Canada maya.saleh@mcgill.ca.
authors.forename: Maya
authors.initials: M
authors.lastname: Saleh
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020170:Caspase 1 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020169:Caspases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D053471:Caspases, Initiator; D003872:Dermatitis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015151:Immunoblotting; D058847:Inflammasomes / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009336:Necrosis / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D012867:Skin / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: D002352:Carrier Proteins; D058847:Inflammasomes; D047908:Intracellular Signaling Peptides and Proteins; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C554944:Sipl1 protein, mouse; C101136:Casp4 protein, mouse; D020169:Caspases; D053471:Caspases, Initiator; D020170:Caspase 1