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STAT5 tetramerization is a central determinant of monocyte fate and colonic pathogenicity

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, whereas STAT5 tetramer deficiency yields a macrophage phenotype. In the dextran sulfate sodium model of colitis, STAT5 tetramer-deficient monocytes exacerbate disease severity. Mechanistically, GM-CSF signaling in STAT5 tetramer-deficient monocytes results in the overexpression arginase I and a reduction in nitric oxide synthesis following stimulation with lipopolysaccharide. Correspondingly, the inhibition of arginase I activity and supplementation with a sustained concentration of nitric oxide ameliorates the worsened colitis in STAT5 tetramer-deficient mice. Thus, this study suggests a protective role of STAT5 tetramers in inflammatory bowel disease through the regulation of arginine metabolism. We previously reported that STAT5 tetramerization in monocytes is detrimental in autoimmune-mediated neuroinflammation. This study highlights the opposing role of STAT5 tetramers in inflammatory bowel disease.

ORGANISM(S): Mus musculus

PROVIDER: GSE207676 | GEO | 2023/04/11

REPOSITORIES: GEO

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Tetramerization of Transcription Factor STAT5 in Monocytes Promotes Autoimmune-mediated Neuroinflammation via the Regulation of CCL17

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