Loss of Antigen Presentation in Adipose Tissue Macrophages or in Adipocytes, but Not Both, Improves Glucose Metabolism
Loss of Antigen Presentation in Adipose Tissue Macrophages or in Adipocytes, but Not Both, Improves Glucose Metabolism
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脂肪组织巨噬细胞或脂肪细胞中抗原呈递的丧失（但不是两者）可改善葡萄糖代谢
DOI：
10.4049/jimmunol.1801470
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发表时间：
2019-04-15
影响因子：
4.4
通讯作者：
Hsueh, Willa A.
中科院分区：
文献类型：
--
作者：
Blaszczak, Alecia M.;Wright, Valerie P.;Hsueh, Willa A.
脂肪细胞和巨噬细胞H2Ab1的缺失导致代谢表型无变化。巨噬细胞H2Ab1的特异性缺失导致葡萄糖耐量的改善。HFD上的脂肪细胞表达LysM，并被LysMCre模型靶向。巨噬细胞、B细胞和脂肪细胞是脂肪组织（AT） apc中分化和激活初始CD4+ T细胞的细胞。脂肪细胞丢失MHC II类（MHC II）的小鼠对胰岛素更敏感。由于巨噬细胞是专业的apc，因此产生了遗传性髓系MHCII缺失（髓系MHCII敲除[mMHCII−/−]）的小鼠并对其进行了代谢表征。FITC+葡聚糖包被颗粒（葡聚糖包被小干扰RNA [siRNA]颗粒[GeRPs]）也被用于特异性靶向AT巨噬细胞（atm）中的MHC II敲除。通过将LyzMCre与H2Ab1捆绑小鼠杂交，产生了全身mMHCII−/−的小鼠。为了使H2Ab1在ATM中特异性消失，将含有H2Ab1 siRNA的GeRPs给予高脂饮食喂养的C57BL/6小鼠。出乎意料的是，mMHCII - / -小鼠巨噬细胞和脂肪细胞H2Ab1均缺失，这是仅有的两个ag呈递臂中的一个；因此，这两种细胞都不能呈递Ag并激活CD4+ T细胞。这种无能导致AT免疫抑制性调节性T细胞减少，AT CD8+ T细胞增加，而全身代谢没有改善。因此，合并系统性髓细胞和脂肪细胞MHC II损失，atm特异性改变对APC活性的影响无法描述。因此，含有H2Ab1 siRNA的GeRPs被施用于特异性降低ATM H2Ab1，相反，显示葡萄糖耐量改善。综上所述，由于AT调节性T细胞的维持，ATM或脂肪细胞APC功能的丧失（而非两者都丧失）可以改善全身葡萄糖代谢。
Key Points Loss of adipocyte and macrophage H2Ab1 leads to no change in metabolic phenotype. Specific loss of macrophage H2Ab1 leads to improvements in glucose tolerance. Adipocytes on HFD express LysM and are targeted by the LysMCre model. Macrophages, B cells, and adipocytes are among the adipose tissue (AT) APCs that differentiate and activate naive CD4+ T cells. Mice with adipocyte loss of MHC class II (MHC II) are more insulin sensitive. Because macrophages are professional APCs, mice with genetic myeloid MHC II depletion (myeloid MHC II knockout [mMHCII−/−]) were created and metabolically characterized. FITC+ glucan-coated particles (glucan-encapsulated small interfering RNA [siRNA] particles [GeRPs]) were also used to target MHC II knockout specifically in AT macrophages (ATMs). Mice with total body mMHCII−/− were generated by crossing LyzMCre with H2Ab1 floxed mice. For specific ATM depletion of H2Ab1, GeRPs containing H2Ab1 siRNA were administered to high-fat diet–fed C57BL/6 mice. Unexpectedly, mMHCII−/− mice had loss of both macrophage and adipocyte H2Ab1, one of only two Ag-presenting arms; thus, neither cell could present Ag and activate CD4+ T cells. This inability led to a reduction in AT immunosuppressive regulatory T cells, increased AT CD8+ T cells, and no improvement in systemic metabolism. Thus, with combined systemic myeloid and adipocyte MHC II loss, the impact of ATM-specific alterations in APC activity could not be delineated. Therefore, GeRPs containing H2Ab1 siRNA were administered to specifically reduce ATM H2Ab1 which, in contrast, revealed improved glucose tolerance. In conclusion, loss of either ATM or adipocyte APC function, but not both, improves systemic glucose metabolism because of maintenance of AT regulatory T cells.