Glutaredoxin 1 controls monocyte reprogramming during nutrient stress and protects mice against obesity and atherosclerosis in a sex-specific manner

Abstract

High-calorie diet-induced nutrient stress promotes thiol oxidative stress and the reprogramming of blood monocytes, giving rise to dysregulated, obesogenic, proatherogenic monocyte-derived macrophages. We report that in chow-fed, reproductively senescent female mice but not in age-matched male mice, deficiency in the thiol transferase glutaredoxin 1 (Grx1) promotes dysregulated macrophage phenotypes as well as rapid weight gain and atherogenesis. Grx1 deficiency derepresses distinct expression patterns of reactive oxygen species and reactive nitrogen species generators in male versus female macrophages, poising female but not male macrophages for increased peroxynitrate production. Hematopoietic Grx1 deficiency recapitulates this sexual dimorphism in high-calorie diet-fed LDLR-/- mice, whereas macrophage-restricted overexpression of Grx1 eliminates the sex differences unmasked by high-calorie diet-feeding and protects both males and females against atherogenesis. We conclude that loss of monocytic Grx1 activity disrupts the immunometabolic balance in mice and derepresses sexually dimorphic oxidative stress responses in macrophages. This mechanism may contribute to the sex differences reported in cardiovascular disease and obesity in humans.

NF‐κB inactivation attenuates the M1 macrophage polarization in experimental necrotizing enterocolitis by glutaredoxin‐1 deficiency

“…Together with this, Grx1 depletion modulated the NF‐κB activation during NEC, events that are perhaps linked with proinflammatory responses, which eventually contributed to protection the intestinal inflammatory injury. Indeed, Grx1 was previously reported to be associated with differentiation of monocyte‐like cells to macrophage lineage (Aesif, Anathy, et al, 2011; Ahn et al, 2022). In our study, the Grx1 − / − derived IMs presented potent anti‐inflammatory activity than WT IMs.…”

Exercise Ameliorates Atherosclerosis via Up-Regulating Serum β-Hydroxybutyrate Levels

“…These cells were plated in 24-well plates and cultured at 37 °C in 5% CO 2 overnight. Non-adherent cells were removed though washing with PBS, leaving adhered peritoneal macrophages [ 67 ]. All PMs were maintained in the culture for 24 hours in RPMI 1640 containing 10% FBS prior to the treatments.…”

GPSM1 impairs metabolic homeostasis by controlling a pro-inflammatory pathway in macrophages

“…Each mouse received two Matrigel plugs three days prior to euthanasia as described 64 , 65 . Briefly, growth factor-reduced Matrigels (354230, BioCoat, R&D Systems) were subcutaneously injected into the right and left flank of each mouse, one plug containing MCP-1 (500 ng/ml) and the other plug containing vehicle.…”