Lnk/Sh2b3 Regulates Adipose Inflammation and Glucose Tolerance through Group 1 ILCs
Lnk/Sh2b3 Regulates Adipose Inflammation and Glucose Tolerance through Group 1 ILCs
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DOI：
10.1016/j.celrep.2018.07.036
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发表时间：
2018-08-14
期刊：
影响因子：
8.8
通讯作者：
Takaki, Satoshi
中科院分区：
文献类型：
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作者：
Mori, Taizo;Suzuki-Yamazaki, Nao;Takaki, Satoshi
link /Sh2b3是淋巴造血过程中负向调节细胞因子信号的接头蛋白。据报道，LNK/SH2B3基因中的错义变异是几种自身免疫性疾病（包括糖尿病）的危险变异。我们发现Lnk(-/)（-）小鼠的葡萄糖耐量和胰岛素反应受损。此外，免疫细胞如1组先天淋巴样细胞（G1-ILCs）、CD8(+) T细胞和M1巨噬细胞在脂肪组织中积累。当Lnk(-/)（-）小鼠与Il15（-/-）小鼠杂交或去除G1-ILCs而非CD8(+) T细胞时，葡萄糖耐受不良和脂肪炎症得到改善。Lnk(-/)(-) G1-ILCs表现出活化的表型以及对IL-15的反应性增强，并且给予JAK抑制剂可改善葡萄糖耐量。因此，高脂肪饮食极大地恶化了Lnk(-/)（-）小鼠的葡萄糖耐受不良。因此，Lnk/Sh2b3通过调节il -15依赖性脂肪G1-ILCs的扩张和激活来控制脂肪组织的内稳态，降低糖尿病发病的风险。
Lnk/Sh2b3 is an adaptor protein that negatively regulates cytokine signaling in lymphohematopoiesis. A missense variant within the LNK/SH2B3 gene has been reported to be a risk variant for several autoimmune diseases, including diabetes. We found that glucose tolerance and insulin responses were impaired in Lnk(-/)(-) mice. Moreover, immune cells such as group 1 innate lymphoid cells (G1-ILCs), CD8(+) T cells, and M1 macrophages accumulated in adipose tissue. When Lnk(-/)(-) mice were crossed with Il15(-/- )mice or depleted of G1-ILCs but not CD8(+) T cells, glucose intolerance and adipose inflammation were ameliorated. Lnk(-/)(-) G1-ILCs showed activated phenotypes as well as enhanced reactivity for IL-15, and administration of a JAK inhibitor improved glucose tolerance. Accordingly, a high-fat diet greatly worsened glucose intolerance in Lnk(-/)(-) mice. Thus, Lnk/Sh2b3 controls homeostasis in adipose tissue and reduces the risk of onset of diabetes by regulating the expansion and activation of IL-15-dependent adipose G1-ILCs.