Loss of Antigen Presentation in Adipose Tissue Macrophages or in Adipocytes, but Not Both, Improves Glucose Metabolism
Program in Molecular Medicine
Cellular and Molecular Physiology | Endocrinology | Immunology and Infectious Disease
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.
DOI of Published Version
J Immunol. 2019 Apr 15;202(8):2451-2459. doi: 10.4049/jimmunol.1801470. Epub 2019 Mar 8. Link to article on publisher's site
Journal of immunology (Baltimore, Md. : 1950)
Blaszczak, Alecia M.; Wright, Valerie P.; Anandani, Kajol; Liu, Joey; Jalilvand, Anahita; Bergin, Stephen; Nicoloro, Sarah M.; Czech, Michael P.; Lafuse, William; Deng, Tuo; Bradley, David; and Hsueh, Willa A., "Loss of Antigen Presentation in Adipose Tissue Macrophages or in Adipocytes, but Not Both, Improves Glucose Metabolism" (2019). Program in Molecular Medicine Publications and Presentations. 106.