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

Cell Death Differ 2019 03 23;26(4):741-750. Epub 2018 Jul 23.

Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.

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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Source
http://dx.doi.org/10.1038/s41418-018-0159-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6460383PMC
March 2019
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