Innate immune adaptor MyD88 deficiency prevents skin inflammation in SHARPIN-deficient mice

Abstract

Mice deficient in SHANK-associated RH domain-interacting protein (SHARPIN), a component of the linear ubiquitin chain assembly complex (LUBAC), develop a spontaneous inflammatory disorder with pathologic hallmarks similar to atopic dermatitis and psoriasis in humans. Previous studies identified the crucial role of components of the TNF and IL-1 signaling pathways in the progression of disease in SHARPIN-deficient mice. However, an innate immune adaptor or sensor that relates to the disease progression has remained unknown. In this study, we found that the genetic ablation of myeloid differentiation primary response 88 (MyD88) completely rescued skin inflammation in SHARPIN-deficient (Sharpin) mice. Systemic inflammation and immune cell dysregulation were partially rescued. Fibroblasts derived from SharpinMyd88 mice failed to provide protection against TNF-induced cell death. SharpinMyd88 mice had reduced TNF production in their skin. Furthermore, depletion of the microbiota through the oral administration of antibiotics (ABX) partially rescued both the skin inflammation and systemic inflammation, demonstrating a role for the gut microbiota in SHARPIN-deficient mice. Our findings suggest a detrimental role for the innate immune adaptor MyD88 in instigating skin inflammation in Sharpin mice.

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“…For immunoblot analysis of signaling components, supernatants were removed, and cells were washed once with PBS, followed by lysis in RIPA buffer and sample loading buffer. Proteins were separated by electrophoresis through 8%-12% polyacrylamide gels (57). Following electrophoretic transfer of proteins onto PVDF membranes (IPVH00010, MilliporeSigma), nonspecific binding was blocked by incubation with 5% skim milk, and then membranes were incubated with primary antibodies against CASP3 (9662, Cell Signaling Technology [CST]), cleaved CASP3 (9661, CST), CASP7 (9492, CST), cleaved CASP7 (9491, CST), CASP8 (AG-20T-0138-C100, AdipoGen), cleaved CASP8 (8592, CST), IRF1 (8478, CST), P-ERK (9101, CST), ERK (9102, CST), P-IκBα (9241, CST), IκBα (9242, CST), P-STAT3 Tyr705 (9131, CST), STAT3 (9139, CST), and…”

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“…Another recent study has determined important roles for RIPK1, TNF, and myeloid differentiation primary response protein 88 (MyD88) signaling in the complete rescue of skin inflammation in Sharpin cpdm mice. [141][142][143] Together, these studies show that Sharpin is a crucial regulator of both apoptotic and necroptotic cell death pathways in epidermal cells. Moreover, these findings have been further strengthened by the demonstration that MyD88 deficiency.…”

“…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. Another recent study has determined important roles for RIPK1, TNF, and myeloid differentiation primary response protein 88 (MyD88) signaling in the complete rescue of skin inflammation in Sharpin cpdm mice . Together, these studies show that Sharpin is a crucial regulator of both apoptotic and necroptotic cell death pathways in epidermal cells.…”

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“…However, the genetic deletions of caspase 8 and Rip3k in mice (Sharpin cpd/cpdm /Casp8 +/− /Rip3k −/− ) completely alleviated the phenotype [62]. Recently, Sharma and coworkers showed that the genetic ablation of MyD88 in Sharpin-deficient cpdm mice (Sharpin cpd/cpdm /Myd88 −/− ) completely and partially rescued the skin lesions and systemic inflammation, respectively [63]. Interestingly, they proposed that gut microbiota may play a role in inflammation induction in cpdm mice.…”