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.

Distinct role of IL-1β in instigating disease in Sharpincpdm mice

“…The NLRP3 inflammasome has also been reported to play a role in instigating skin inflammation in Sharpin cpdm mice9. In comparison to Sharpin cpdm mice, Sharpin cpdm  ×  Nlrp3 −⁄− and Sharpin cpdm  ×  Casp1 −⁄−  ×  Casp11 −⁄− mice display a delayed onset of clinical signs of dermatitis9.…”

Genome-Wide Association Study of Cell-Mediated Response in Dogs Naturally Infected by Leishmania infantum

“…SHARPIN also appeared as a potential candidate affecting the LST response. This gene encodes a SHANK-associated RH domain-interacting protein, which is a regulatory subunit crucial to the catalytic activity of the complex LUBAC (linear ubiquitin assembly complex), which plays a critical role in the activation of NF-B (43). A spontaneous mutation in the gene SHARPIN was shown to lead to multiorgan inflammation, including dermatitis in mice (44).…”

Autoinflammatory Skin Disorders: The Inflammasome in Focus

“…Similarly, IL-1R-deficiency also delays dermatitis and onset of disease in Sharpin cpdm mice [87]. A recent study reported that skin tissues of Sharpin cpdm mice exhibited dramatically increased levels of the inflammasome-regulated cytokines IL-1β and IL-18 cytokines [88]. Western blot analysis revealed that diseased skin samples also have increased caspase-1 activation, directly implicating the inflammasome in the regulation of these cytokines as well as in Sharpin cpdm mice skin inflammation.…”

“…Western blot analysis revealed that diseased skin samples also have increased caspase-1 activation, directly implicating the inflammasome in the regulation of these cytokines as well as in Sharpin cpdm mice skin inflammation. Furthermore, genetic ablation of either NLRP3 or caspase-1 in Sharpin cpdm mice has been found to reduce IL-1β and IL-18 cytokines to levels similar to that of WT and, importantly, delaying the disease phenotype [88]. Thus, SHARPIN could have cell-specific roles, where SHARPIN might be promoting NLRP3 inflammasome activation in myeloid cells, while inhibiting NLRP3 inflammasome activation in skin cells.…”

“…Although NLRP3 inflammasome and IL-1 signaling deficiencies significantly reduce skin inflammation and delay the onset of skin disease symptoms [86–88], Sharpin cpdm inflammasome-component deficient mice still develop a full spectrum of disease, suggesting that the IL-1 signaling pathway may play only a minor role in disease progression.…”