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.
PLoS One. 2018 Sep 18;13(9):e0203952. doi: 10.1371/journal.pone.0203952. eCollection 2018.
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有关。我们生成了可诱导敲除（KO）的 Clec16a 小鼠，以研究 CLEC16A 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。Clec16a KO 小鼠的脾细胞中线粒体潜能降低，导致 B、T 和 NK 细胞中不健康的线粒体聚集。在 Clec16a KO 小鼠中，我们检测到脾脏 B 和 T 细胞中的自噬作用受损。Clec16a KO 小鼠的 NK 细胞表现出增强的细胞毒性。PI3K 和/或 MEK 抑制可减轻 Clec16a KO 小鼠中的不完全自噬。我们的研究结果表明 CLEC16A 与免疫细胞中受损的自噬之间存在功能联系，并表明不完全自噬使 KO 小鼠易发生炎症。总之，与 CLEC16A 表达水平降低相关的 CLEC16A 功能丧失变体可能通过受损的自噬作用导致自身免疫中的炎症。调节自噬的药物可逆转该过程，并可能对具有相关 CLEC16A 变体风险的个体的自身免疫治疗和预防有效。
