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Deoxyhypusine Synthase Promotes a Pro-Inflammatory Macrophage Phenotype

ABSTRACT: Obesity is characterized by adipose tissue expansion, macrophage infiltration, and the development of chronic low-grade meta-inflammation that drives insulin resistance and metabolic dysfunction. Eukaryotic translation initiation factor 5A (eIF5A) is the only protein known to be uniquely post-translationally modified and activated by deoxyhypusine synthase (DHPS) to generate a hypusine (Hyp) residue. Activated eIF5A controls the translation of a subset of mRNAs that play a role in inflammation, but a role for the DHPS/eIF5AHyp axis in obesity-associated adipose tissue inflammation has not been tested. We found DHPS/eIF5AHyp levels to be increased in the stromal vascular fraction of adipose tissue from mice fed a high fat diet and in murine macrophages activated to a proinflammatory M1 phenotype. DHPS deficiency in M1 macrophages decreased global mRNA translation and protein synthesis of key inflammatory mediators, IL-1β and MIP-1α. Transcriptomes of LPS+IFN-γ-stimulated DHPS-deficient macrophages revealed reduced characteristics of an M1 signature and a phenotypic switch consistent with characteristics of an anti-inflammatory M2 signature. In support of these observations, macrophage migration in a zebrafish tailfin injury model was reduced with chemical inhibition of DHPS, and DHPS deficiency in myeloid cells of HFD-fed mice inhibited M1 macrophage accumulation in adipose tissue and improved glucose tolerance. Together, these findings indicate that DHPS is required for the translation of a subset of mRNAs required for inflammation and chemotaxis in macrophages and may contribute to a proinflammatory M1-like phenotype.

ORGANISM(S): Mus musculus

PROVIDER: GSE144614 | GEO | 2021/09/15

REPOSITORIES: GEO

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Project description:Recent 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. F4/80-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. Transcriptome 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. Our 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.

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Deoxyhypusine Synthase Promotes a Pro-Inflammatory Macrophage Phenotype

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