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

Bhesh Raj Sharma, Rajendra Karki, Ein Lee, Qifan Zhu, Prajwal Gurung, Thirumala-Devi Kanneganti
2018 Cell Death and Differentiation  
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
more » ... 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 cpdm ) mice. Systemic inflammation and immune cell dysregulation were partially rescued. Fibroblasts derived from Sharpin cpdm Myd88 −⁄− mice failed to provide protection against TNF-induced cell death. Sharpin cpdm Myd88 −⁄− 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 cpdm mice.
doi:10.1038/s41418-018-0159-7 pmid:30038386 fatcat:2iw4cpd5ovesvbalpa64coqg6q