GSE193613
Glucosamine facilitates cardiac ischemic recovery via recruiting Ly6Clow monocytes in a STAT1 O-GlcNAcylation dependent fashion
The O-linked ß-N-acetylglucosamine (O-GlcNAc) modification on intracellular proteins controls diverse biological processes. Though sustained hyper-O-GlcNAcylation aggravates pathogenesis of many chronic diseases, accumulating evidence also indicates that acute augmentation in O-GlcNAcylation seems to benefit disease healing in some cases. Glucosamine (GlcN) is a freely available and commonly used dietary supplement for human cartilage health, which also activates the hexosamine biosynthesis pathway and induces protein O-GlcNAcylation. Here we show that both GlcN early and late therapies effectively facilitate cardiac recovery in mice by elevating accumulation of Ly6Clow Mo/Mps in infarcted hearts. Eliminating Mo/Mps with clodronate liposomes fully abolishes aforementioned cardiac healing role of GlcN. Importantly, GlcN supplementation accelerates not only in vitro mobility of reparative Mo/Mps but also in vivo infiltration of Ly6Clow Mos. Mechanistically, GlcN positively regulates transcription of myeloid CX3C chemokine receptor 1 (Cx3cr1) by improving STAT1 O-GlcNAcylation, which stabilizes STAT1 and subsequently promotes chemotaxis and infiltration of Ly6Clow Mos. In summary, we identify a novel anti-inflammatory role of GlcN and suggest that its protective effects are mediated through chemotaxis of Ly6Clow Mos in a STAT1/CX3CR1-dependent fashion, which is controlled by O-GlcNAcylation of STAT1. Our study provides a novel clue for Mo/Mps modulator therapies aimed at reducing post-MI hyperinflammation in ischemic myocardium. Overall design: Ischemic zones from GlcN/E or saline hearts on Day 3 post-MI