TGM2-deficient macrophages exhibited a significant upregulation of pro-inflammatory signatures.

Macrophages are essential for tissue homeostasis, orchestrating the initiation and resolution of both innate and adaptive immunity with profound impacts on protective immunity and immune-mediated pathological damage. Macrophages are heterogeneous subsets. During the inflammatory response, they include both pro-inflammatory subsets and subsets that promote inflammation resolution, and different macrophage subsets play distinct roles in the dynamic processes at different time points. In the current study, we found that a subset of TGM2+ macrophages with inflammation-resolving properties gradually increases during the inflammation resolution phase in the LPS-induced endotoxin shock model. The peak expression of the TGM2 gene occurs mainly during the inflammation resolution phase. Additionally, transcriptome analysis revealed that compared with wild-type (WT) macrophages, TGM2-deficient macrophages exhibited a significant upregulation of pro-inflammatory signatures and a marked downregulation of lipid metabolic synthesis processes. In lipid rescue experiments, we found that the elevated inflammation phenotype of TGM2-deficient macrophages could be restored. Moreover, a significant anti-inflammatory function of this macrophage subset was observed in mouse models of severe disease, enterocolitis, and endotoxin shock. We uncover an inflammatory remodeling of the neuro-metabolic landscape in macrophages, whereby serotonin induces TGM2-mediated serotonylation of in AKT1.