Glutaredoxin 1 facilitates colitis recovery by controlling glutathionylation and activity of STAT6 in M2 macrophages

Abstract

Inflammatory bowel disease (IBD) is characterized by oxidative stress and intractable inflammation. Current therapeutic strategies are far from satisfactory because of its not fully understood pathogenesis. M2 macrophages can promote inflammation resolution and tissue repair, and are attractive therapeutic targets of IBD. However, the intrinsic nature of redox regulation of M2 macrophages in IBD is still elusive. DSS-induced murine colitis recovery model and GEO data suggest that glutaredoxin 1 (Grx1) might be the main redox modulator of macrophages in IBD. Grx1 is the main enzyme negatively catalyzing ROS-elicited protein glutathionylation. Depletion of Grx1 delays colitis recovery, while recombinant Grx1 protein treatment benefits colitis recovery, with decreased glutathionylation and increased M2 macrophages. Grx1-deficient IL-4-polarized macrophages show reduced pro-repair effects on injured intestinal epithelial tight junctions, impaired efferocytosis, and compromised maintenance of the M2-polarized state. Mechanistically, STAT6, a pivotal transcription factor in M2 macrophages, is proved to be the main target of Grx1 and glutathionylation. Grx1 disruption decreases nuclear translocation of STAT6 in macrophages, while mutation of modified cysteine in STAT6 displays reverse effect. Finally, Grx1-STAT6 signaling is verified in colitis recovery models. Our results reveal Grx1/glutathionylation as crucial negative redox regulatory mechanisms of M2 macrophages in IBD, which exhibits promising therapeutic potential of IBD.