Adipose Tissue Immunosuppressive T Cells Regulate Atherosclerosis Development and Liver Fat Accumulation in Obesity
Alecia M. Blaszczak, Dharti Shantaram, Xilal Y. Rima, Valerie P. Wright, Joey Liu, Alan J. Smith, Anahita Jalilvand, Anastasiia Amari, Chase D. Bender, Dana Middendorf, Regina Gebhardt, Martha M. Yearsley, Debasish Roy, Edward A. Fisher, David Bradley, Willa A. HsuehBACKGROUND:
Obesity is associated with a loss of anti-inflammatory regulatory T cells (Tregs) in adipose tissue (AT), resulting in systemic inflammation. The adipocyte is a central modulator of CD4+T-cell subpopulations via antigen presentation through the MHCII (major histocompatibility complex class II). However, the role of adipocyte-induced AT inflammation due to changes in AT Tregs in obesity-related complications, such as atherosclerosis and metabolic-dysfunction-associated fatty liver disease (MAFLD), remains unknown.
METHODS:
Ldlr (low-density lipoprotein receptor) −/− knockout mice were crossed with adipocyte-specific MHCII knockout (aMHCll [adipocyte MHCII] −/− ) mice to study the effects of AT T-cell changes on atherosclerosis and MAFLD. Metabolic differences, atherosclerotic lesions, liver fat accumulation, and inflammation in adipose, splenic, aortic, and liver tissue were measured in 1-year-old aMHCll −/− Ldlr −/− mice fed a Western high-fat diet for 12 weeks. We used 1-year-old mice because, unlike young mice, they develop markedly accelerated atherosclerosis like humans.
RESULTS:
Loss of MHCII signaling in adipocytes prevented the obesity-mediated loss of AT Tregs, resulting in decreased insulin resistance, atherosclerosis, and MAFLD. In contrast, depletion of AT Tregs via IL (interleukin)-33 receptor–targeted immunotherapy with ST2 (suppression of tumorigenicity 2) reversed these improvements in Western high-fat diet–fed, 1-year-old aMHCll −/− Ldlr −/− mice, whereas increasing AT Tregs with IL-33 recombinant protein promoted similar beneficial effects as in aMHCll −/− Ldlr −/− mice. Because there were no alterations in splenic Tregs, these differences in atherosclerosis and MAFLD were AT Treg-mediated, independent of peripheral Tregs. Amelioration of insulin resistance, atherosclerosis, and MAFLD was diet- and adipocyte-dependent, as a low-fat, Western diet administered to 1-year-old aMHCll −/− Ldlr −/− mice and myeloid-adipo–specific MHCII knockout mice (m-aMHCll [myeloid-adipocyte MHCII] −/− ) ingesting a Western high-fat diet, had no effect on disease progression.
CONCLUSIONS:
These results suggest that AT immunosuppressive T cells play a pivotal role in regulating both atherosclerosis development and liver fat accumulation in obesity.