Tetramerization of STAT5 regulates monocyte differentiation and the dextran sulfate sodium-induced colitis in mice

Abstract

In response to external stimuli during immune responses, monocytes can have multifaceted roles such as pathogen clearance and tissue repair. However, aberrant control of monocyte activation can result in chronic inflammation and subsequent tissue damage. Granulocyte-macrophage colony-stimulating factor (GM-CSF) induces monocyte differentiation into a heterogenous population of monocyte-derived dendritic cells (moDCs) and macrophages. However, the downstream molecular signals that dictate the differentiation of monocytes under pathological conditions is incompletely understood. We report here that the GM-CSF-induced STAT5 tetramerization is a critical determinate of monocyte fate and function. Monocytes require STAT5 tetramers to differentiate into moDCs. Conversely, the absence of STAT5 tetramers results in a switch to a functionally distinct monocyte-derived macrophage population. In the dextran sulfate sodium (DSS) model of colitis, STAT5 tetramer-deficient monocytes exacerbate disease severity. Mechanistically, GM-CSF signaling in STAT5 tetramer-deficient monocytes results in the overexpression of arginase I and a reduction in nitric oxide synthesis following stimulation with lipopolysaccharide. Correspondingly, the inhibition of arginase I activity and sustained supplementation of nitric oxide ameliorates the worsened colitis in STAT5 tetramer-deficient mice. This study suggests that STAT5 tetramers protect against severe intestinal inflammation through the regulation of arginine metabolism.

Effects of Bacillus coagulans TBC169 on gut microbiota and metabolites in gynecological laparoscopy patients

“…BCTL treatment might enhance the absorption and utilization of Glu in the intestine, contributing to the maintenance of intestinal balance and accelerated recovery of intestinal function following GLs. According to previous studies, there was a correlation between arginine consumption and inflammation in colon ( Monaghan et al, 2023 ). In the study, BCTL might protect against intestinal inflammation through the down-regulation of Arg-Try, and the up-regulation of Arg-Phe-Arg.…”

Origin and Function of Monocytes in Inflammatory Bowel Disease

“…Aberrations in these tetramers shift differentiation towards functionally distinct moMφs, with heightened arginase I expression and reduced LPS-induced NO synthesis. 99 A noteworthy observation is that moMφs, when treated with GH within a GM-CSF milieu, demonstrate a pronounced bias towards anti-inflammatory gene signatures. This shift is attributed to a decline in activin A mediated via the PI3K pathway and an upsurge in MAFB expression, collectively impeding the polarization towards pro-inflammatory macrophages.…”

“…Contextualizing this within the broader cytokine-mediated modulation landscape, it is postulated that IRF4 may function downstream of the STAT5 tetramer assembly, though this intricate mechanism merits comprehensive exploration. 99,102 Moreover, the genetic backdrop characterized by miR-223 deficiency manifests in a pronounced decrement in the CR3CX1 + MΦ population, contrasted by an augmentation in moDCs differentiation trajectory. 103 Recent discoveries underscore that in monocytes, NOD2 activation exerts an inhibitory effect on macrophage differentiation, operating through the mTOR signaling cascade and modulated by the TNF-α axis.…”