Dataset Information

CD11c^-MHC2^low Macrophages Are a New Inflammatory and Dynamic Subset in Murine Adipose Tissue.

ABSTRACT:

Background

The prevalence of obesity is rising and leads to increased morbidity and mortality. Adipose tissue inflammation, due to accumulation and activation of adipose tissue macrophages (ATMs), is a key driver of this phenomenon. Macrophages are heterogeneous cells, adapting quickly to the microenvironment, resulting in so-called M1 or M2 macrophages. In this study, we describe the dynamics and inflammatory properties of a newly identified ATM subset in obese mice.

Methods

LDLR^-/- mice received a high fat diet (HFD) for 5 weeks or 16 weeks to induce obesity. Adipose tissues were isolated and immune cell subsets were analyzed with flow cytometry or microarray analysis. Bone marrow transplantation (BMT) using CD45.1 and CD45.2 LDLR^-/- mice was performed to determine ATM origin.

Results

Upon HFD, there is a massive increase of ATM subsets in the adipose tissue. CD11c^-M2 ATMs could be subdivided based on their MHC2 expression into CD11c^-MHC2^high ATMs and previously unidentified CD11c^-MHC2^low ATMs. CD11c^-MHC2^low ATMs accumulated very rapidly after 10 days of HFD, after which they increased even further with prolonged HFD. Microarray data showed that CD11c^-MHC2^low ATMs resembled CD11c^-MHC2^high ATMs in the steady state, but became more inflammatory during development of obesity. In vitro stimulation of bone marrow-derived macrophages with palmitate, abundantly present in HFD, resulted in the induction of the CD11c^-MHC2^low phenotype.

Conclusions

Among M2 macrophages, a novel pro-inflammatory subset of macrophages was found based on their low level of MHC2 expression. This subset may play a role in the development of adipose tissue inflammation.

SUBMITTER: Wetzels S

PROVIDER: S-EPMC7612162 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Aims/hypothesisRecent studies have identified intracellular metabolism as a fundamental determinant of macrophage function. In obesity, proinflammatory macrophages accumulate in adipose tissue and trigger chronic low-grade inflammation, that promotes the development of systemic insulin resistance, yet changes in their intracellular energy metabolism are currently unknown. We therefore set out to study metabolic signatures of adipose tissue macrophages (ATMs) in lean and obese conditions.MethodsF4/80-positive ATMs were isolated from obese vs lean mice. High-fat feeding of wild-type mice and myeloid-specific Hif1α-/- mice was used to examine the role of hypoxia-inducible factor-1α (HIF-1α) in ATMs part of obese adipose tissue. In vitro, bone marrow-derived macrophages were co-cultured with adipose tissue explants to examine adipose tissue-induced changes in macrophage phenotypes. Transcriptome analysis, real-time flux measurements, ELISA and several other approaches were used to determine the metabolic signatures and inflammatory status of macrophages. In addition, various metabolic routes were inhibited to determine their relevance for cytokine production.ResultsTranscriptome analysis and extracellular flux measurements of mouse ATMs revealed unique metabolic rewiring in obesity characterised by both increased glycolysis and oxidative phosphorylation. Similar metabolic activation of CD14+ cells in obese individuals was associated with diabetes outcome. These changes were not observed in peritoneal macrophages from obese vs lean mice and did not resemble metabolic rewiring in M1-primed macrophages. Instead, metabolic activation of macrophages was dose-dependently induced by a set of adipose tissue-derived factors that could not be reduced to leptin or lactate. Using metabolic inhibitors, we identified various metabolic routes, including fatty acid oxidation, glycolysis and glutaminolysis, that contributed to cytokine release by ATMs in lean adipose tissue. Glycolysis appeared to be the main contributor to the proinflammatory trait of macrophages in obese adipose tissue. HIF-1α, a key regulator of glycolysis, nonetheless appeared to play no critical role in proinflammatory activation of ATMs during early stages of obesity.Conclusions/interpretationOur results reveal unique metabolic activation of ATMs in obesity that promotes inflammatory cytokine release. Further understanding of metabolic programming in ATMs will most likely lead to novel therapeutic targets to curtail inflammatory responses in obesity.Data availabilityMicroarray data of ATMs isolated from obese or lean mice have been submitted to the Gene Expression Omnibus (accession no. GSE84000).

Project description:BackgroundIncreased CD11c+ Mφ aggravates colonic mucosal injuries in ulcerative colitis (UC) with TSP1 protein increased. The thrombospondin-1 (TSP1) protein which could activate Mφ is closely related to the colonic mucosal damage in UC. Here, we investigated the role of TSP1 in the differentiation of CD11c+ Mφ and the mechanism.MethodsWe analyzed the population characteristics of TSP1 genes using the Genotype-Tissue Expression (GTEx) database, and human serum TSP1 protein was detected with ELISA. DSS-induced colitis rats were used to explore the effects of TSP1 on colonic mucosal inflammation. We analyzed the serum cytokines and tissue histopathology to evaluate the severity of UC. Furthermore, we analysed the main source of TSP1 in colon tissue. In vitro, lamina propria mononuclear cells (LPMC) and CD11c+ lamina propria macrophages (LPMP) was isolated from model rats in vivo. The target of TSP1 protein was assessed by LSKL, CD36 and CD47 interfering plasmids. The proteins, the lysosome, lysosomal activity and Cathepsin E activity, and the migration were detected by western blotting, test kits and Transwell.ResultsThe expression of TSP1 was significantly higher in younger, male, and in the rectum and sigmoid than that in older, females, and colon tissues, and was closely related to the severity of UC. Compared with normal rats, the worse disease activity index (DAI) score, more histological damage, CD11c+ Mφ infiltration, and increased expression of several proinflammatory cytokines was displayed in colitis rats with the elevation of serum TSP1 protein. In vitro, TSP1 protein derived from cmMφ and endothelial cells promoted the migration and the differentiation of CD11c+ Mφ via binding on CD36, rather than the cell proliferation. Furthermore, PRKCQ/NF-κB signaling pathway was activated by CD36. However, the effect of TSP1 protein could be reversed by LSKL in vivo, and LSKL and anti-TSP1 antibody in vitro.ConclusionsTSP1 promotes the migration and the differentiation of CD11c+ LPMP with lysosomal activity limited via activating the CD36-PRKCQ/NF-κB signaling pathway, which aggravates the colonic mucosal inflammatory injuries in UC.

Dataset Information

CD11c^-MHC2^low Macrophages Are a New Inflammatory and Dynamic Subset in Murine Adipose Tissue.

Background

Methods

Results

Conclusions

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

CD11c-MHC2low Macrophages Are a New Inflammatory and Dynamic Subset in Murine Adipose Tissue.

Background

Methods

Results

Conclusions

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

CD11c^-MHC2^low Macrophages Are a New Inflammatory and Dynamic Subset in Murine Adipose Tissue.