Glutaredoxin 1 Deficiency Causes Late-Age Onset Metabolic Disease in Female C57BL/6 Mice, Associated with Monocyte and Macrophage Dysfunction

Abstract

Glutaredoxin 1 (Grx1) reduces mixed disulfides between glutathione and protein thiols thereby controlling thiol-redox regulated cellular functions, including intracellular signaling, migration, angiogenesis, autophagy and apoptosis. Grx1 protects monocytes and macrophages from metabolic-stress-induced “priming’ and dysfunction. Here we report that female but not male Grx1-/- mice on a C57BL/6 background fed a normal chow diet become obese and hyperglycemic by 6 and 8 months of age respectively. At 18 months female Grx1-/- mice developed spontaneous atherosclerosis and late-age onset associated metabolic disease, characterized by mild hyperlipidemia, hyperglycemia and obesity. Atherosclerotic lesions in 18 month female Grx1-/- mice, measured by en-face analysis, were localized to both the ascending arch and abdominal aortic regions. In aged female Grx1-/- mice, monocyte priming was also measured in vivo using the Matrigel plug assay and ex vivo in multi-well Boyden chambers using peritoneal macrophages isolated from female Grx1-/- mice and age-matched WT mice. Furthermore, aged Grx1-/- female mice possessed increased numbers of circulating Ly6Chi inflammatory blood monocytes compared to male Grx1-/- and WT mice. Macrophages isolated from female Grx1-/- mice also displayed increased protein-S-glutathionylation, increased expression of pro-inflammatory “M1”-associated genes, increased susceptibility to ketocholesterol-induced apoptosis, and impaired autophagy. Together, these data underscore the critical role of protein-S-glutathionylation in monocyte macrophage dysfunction and the development of atherosclerosis and obesity and identify a protective role for Grx1 in these processes. Monocytic Grx1 and metabolic stress-induced protein-S glutathionylation may therefore represent a new mechanistic link between metabolic disorders and chronic inflammatory diseases.