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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE313189 | GEO | 2025/12/15

REPOSITORIES: GEO

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Project description:Dunster2014 - WBC Interactions (Model1) This is a sub-model of a three-step inflammatory response modelling study. The model includes distinct populations of white blood cells namely, macrophages and active and apoptotic neutrophil populations. Neutrophil apoptosis rate is predicted to be crucial for the qualitative nature of the system. This model is described in the article: The resolution of inflammation: a mathematical model of neutrophil and macrophage interactions. Dunster JL, Byrne HM, King JR. Bull. Math. Biol. 2014 Aug; 76(8): 1953-1980 Abstract: There is growing interest in inflammation due to its involvement in many diverse medical conditions, including Alzheimer's disease, cancer, arthritis and asthma. The traditional view that resolution of inflammation is a passive process is now being superceded by an alternative hypothesis whereby its resolution is an active, anti-inflammatory process that can be manipulated therapeutically. This shift in mindset has stimulated a resurgence of interest in the biological mechanisms by which inflammation resolves. The anti-inflammatory processes central to the resolution of inflammation revolve around macrophages and are closely related to pro-inflammatory processes mediated by neutrophils and their ability to damage healthy tissue. We develop a spatially averaged model of inflammation centring on its resolution, accounting for populations of neutrophils and macrophages and incorporating both pro- and anti-inflammatory processes. Our ordinary differential equation model exhibits two outcomes that we relate to healthy and unhealthy states. We use bifurcation analysis to investigate how variation in the system parameters affects its outcome. We find that therapeutic manipulation of the rate of macrophage phagocytosis can aid in resolving inflammation but success is critically dependent on the rate of neutrophil apoptosis. Indeed our model predicts that an effective treatment protocol would take a dual approach, targeting macrophage phagocytosis alongside neutrophil apoptosis. This model is hosted on BioModels Database and identified by: BIOMD0000000616. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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

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