Elsevier

Molecular Metabolism

Volume 7, January 2018, Pages 23-34
Molecular Metabolism

Original Article
Macrophages sensing oxidized DAMPs reprogram their metabolism to support redox homeostasis and inflammation through a TLR2-Syk-ceramide dependent mechanism

https://doi.org/10.1016/j.molmet.2017.11.002Get rights and content
Under a Creative Commons license
open access

Highlights

  • Mox macrophages have a unique metabolism compared to M1 and M2, characterized by suppressed respiration and aerobic glycolysis.

  • Oxidized phospholipids (OxPL) redirect glucose metabolism and TCA metabolites to GSH synthesis in macrophages.

  • Macrophages sensing OxPL upregulate sets of genes via Hif1α and Nrf2.

  • OxPL induce inflammatory gene expression and inhibit respiration in macrophages via a TLR2-Syk-ceramide mechanism.

Abstract

Objective

Macrophages control tissue homeostasis and inflammation by sensing and responding to environmental cues. However, the metabolic adaptation of macrophages to oxidative tissue damage and its translation into inflammatory mechanisms remains enigmatic.

Methods

Here we identify the critical regulatory pathways that are induced by endogenous oxidation-derived DAMPs (oxidized phospholipids, OxPL) in vitro, leading to formation of a unique redox-regulatory metabolic phenotype (Mox), which is strikingly different from conventional classical or alternative macrophage activation.

Results

Unexpectedly, metabolomic analyses demonstrated that Mox heavily rely on glucose metabolism and the pentose phosphate pathway (PPP) to support GSH production and Nrf2-dependent antioxidant gene expression. While the metabolic adaptation of macrophages to OxPL involved transient suppression of aerobic glycolysis, it also led to upregulation of inflammatory gene expression. In contrast to classically activated (M1) macrophages, Hif1α mediated expression of OxPL-induced Glut1 and VEGF but was dispensable for Il1β expression. Mechanistically, we show that OxPL suppress mitochondrial respiration via TLR2-dependent ceramide production, redirecting TCA metabolites to GSH synthesis. Finally, we identify spleen tyrosine kinase (Syk) as a critical downstream signaling mediator that translates OxPL-induced effects into ceramide production and inflammatory gene regulation.

Conclusions

Together, these data demonstrate the metabolic and bioenergetic requirements that enable macrophages to translate tissue oxidation status into either antioxidant or inflammatory responses via sensing OxPL. Targeting dysregulated redox homeostasis in macrophages could therefore lead to novel therapies to treat chronic inflammation.

Keywords

Oxidized phospholipids
Spleen tyrosine kinase
Macrophages
Bioenergetics
Cellular metabolism
Redox homeostasis
Inflammation
Ceramides

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