Publication in detail

PLoS One. 2018 Sep 18;13(9):e0203952. doi: 10.1371/journal.pone.0203952. eCollection 2018.

CLEC16A regulates splenocyte and NK cell function in part through MEK signaling.

Pandey, R; Bakay, M; Hain, HS; Strenkowski, B; Elsaqa, BZB; Roizen, JD; Kushner, JA; Orange, JS; Hakonarson, H

The Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, United States of America. Department of Medicine, Jordan University of Science and Technology, Irbid, Jordan. Division of Endocrinology and Diabetes Children's Hospital of Philadelphia, Philadelphia, PA, United States of America. Section of Pediatric Diabetes and Endocrinology, Department of Pediatric Medicine, Endocrine-Metabolism, Texas Children's Hospital, Houston, TX, United States of America. Section of Immunology, Allergy, and Rheumatology, Department of Pediatric Medicine, Texas Children's Hospital, Houston, TX, United States of America. Department of Pediatrics, the Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States of America.

CLEC16A is implicated in multiple autoimmune diseases. We generated Clec16a inducible knockout (KO) mice to examine the functional link between CLEC16A auto-inflammation and autoimmunity. Clec16a KO mice exhibited weight loss and thymic and splenic atrophy. Mitochondrial potential was lowered in KO mice splenocytes resulting in aggregation of unhealthy mitochondria in B, T, and NK cells. In Clec16a KO mice we detected disrupted mitophagy in splenic B and T cells. NK cells from Clec16a KO mice exhibited increased cytotoxicity. Incomplete mitophagy was attenuated with PI3K and/or MEK inhibition in Clec16a KO mice. Our results demonstrate a functional link between CLEC16A and disrupted mitophagy in immune cells and show that incomplete mitophagy predisposes the KO mice to inflammation. Taken together, loss of function variants in CLEC16A that are associated with decreased CLEC16A expression levels may contribute to inflammation in autoimmunity through disrupted mitophagy. Drugs modulating mitophagy reverse the process and may be effective in treating and preventing autoimmunity in individuals with risk associated CLEC16A variants.

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