Glutamine metabolism suppresses neutrophil recruitment via epigenetic regulation to control inflammatory resolution and skin repair [Multiomic]

Tissue repair requires the resolution of inflammation. However, the molecular mechanisms that attenuate inflammation in vivo are not fully understood. Here, we identify that glutamine metabolism suppresses neutrophil recruitment to abrogate inflammation and drive tissue repair. Integrated metabolomic and transcriptional profiling identified glutamine metabolism as a key feature of macrophages during inflammatory resolution. Dietary depletion studies and conditional deletion of glutaminase (Gls), the essential enzyme involved in glutamine metabolism, in innate immune cells in mice reveals an essential role for glutamine metabolism in suppressing inflammation and promoting tissue repair. Genes involved in neutrophil recruitment are upregulated in macrophages lacking Gls and in foot ulcers of diabetic patients. Multimodal single cell transcriptomics and epigenomics reveals that Gls is required for chromatin remodeling of neutrophil recruitment genes in innate immune cells during resolution of inflammation. These findings highlight the role of glutamine metabolism in controlling cellular communication during tissue repair and suppressing neutrophil recruitment to advance inflammation resolution.