Acquired
aplastic anemia is an immune-mediated disease, in which T cells target hematopoietic cells; at presentation, the bone marrow is replaced by fat. It was reported that bone marrow adipocytes were negative regulators of hematopoietic microenvironment. To examine the role of adipocytes in
bone marrow failure, we investigated peroxisomal proliferator-activated receptor
gamma, a key
transcription factor in adipogenesis, utilizing an antagonist of this factor called
bisphenol-A-diglycidyl-ether. While
bisphenol-A-diglycidyl-ether inhibited adipogenesis as expected, it also suppressed T cell infiltration of bone marrow, reduced plasma inflammatory
cytokines, decreased expression of multiple
inflammasome genes, and ameliorated marrow failure. In vitro,
bisphenol-A-diglycidyl-ether suppressed activation and proliferation, and reduced
phospholipase C gamma 1 and nuclear factor of activated T-cells 1 expression, as well as inhibiting
calcium flux in T cells. The in vivo effect of
bisphenol-A-diglycidyl-ether on T cells was confirmed in a second immune-mediated
bone marrow failure model, using different strains and non-major
histocompatibility antigen mismatched:
bisphenol-A-diglycidyl-ether ameliorated marrow failure by inhibition of T cell infiltration of bone marrow. Our data indicate that peroxisomal proliferator-activated receptor gamma antagonists may attenuate murine immune-mediated
bone marrow failure, at least in part, by suppression of T cell activation, which might hold implications in the application of peroxisomal proliferator-activated receptor gamma antagonists in immune-mediated pathophysiologies, both in the laboratory and in the clinic. Genetically "fatless" mice developed
bone marrow failure with accumulation of marrow adipocytes in our model, even in the absence of body fat, suggesting different mechanisms of systematic and marrow adipogenesis and physiologic versus pathophysiologic fat accumulation.