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

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.CLEC16A与多种自身免疫性疾病存在关联。本研究构建了Clec16a诱导型敲除（KO）小鼠模型，以探究CLEC16A相关自身炎症与自身免疫之间的功能联系。Clec16a KO小鼠表现出体重减轻，以及胸腺和脾脏萎缩。KO小鼠的脾淋巴细胞线粒体电位降低，导致B细胞、T细胞和自然杀伤（Natural Killer, NK）细胞中异常线粒体聚集。我们在Clec16a KO小鼠的脾脏B细胞和T细胞中检测到线粒体自噬（mitophagy）功能紊乱。Clec16a KO小鼠的NK细胞细胞毒性显著增强。在Clec16a KO小鼠中，通过抑制磷脂酰肌醇3-激酶（Phosphatidylinositol 3-kinase, PI3K）和/或丝裂原活化蛋白激酶激酶（Mitogen-Activated Protein Kinase Kinase, MEK）可缓解不完全线粒体自噬现象。本研究结果证实了CLEC16A与免疫细胞中线粒体自噬功能紊乱之间的功能关联，并表明不完全线粒体自噬会使KO小鼠易于发生炎症。综上，CLEC16A表达水平降低相关的CLEC16A功能丧失变异，可能通过破坏线粒体自噬参与自身免疫性炎症的发生发展。调控线粒体自噬的药物可逆转该病理过程，有望用于治疗和预防携带CLEC16A风险变异个体的自身免疫性疾病。