Polarization of Human Macrophages by Interleukin-4 Does Not Require ATP-Citrate Lyase

Namgaladze, Dmitry; Zukunft, Sven; Schnütgen, Frank; Kurrle, Nina; Fleming, Ingrid; Fuhrmann, Dominik C.; Brüne, Bernhard

doi:10.3389/fimmu.2018.02858

Cited by 30 publications

(31 citation statements)

References 45 publications

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“…The difference between our observations and the ones of Lauterbach et al might be explained by the knockdown method (i.e., short-term siRNA vs long-term LysMCre-driven) and other experimental variables. Clearly, the role of Acly in macrophages is stimulus-and time-dependent and also appears to depend on the experimental setting as Namgaladze et al observed no effect of Acly silencing 44 . As such, this is an area that warrants future research.…”

Section: Discussionmentioning

confidence: 99%

Macrophage ATP citrate lyase deficiency stabilizes atherosclerotic plaques

et al. 2020

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Macrophages represent a major immune cell population in atherosclerotic plaques and play central role in the progression of this lipid-driven chronic inflammatory disease. Targeting immunometabolism is proposed as a strategy to revert aberrant macrophage activation to improve disease outcome. Here, we show ATP citrate lyase (Acly) to be activated in inflammatory macrophages and human atherosclerotic plaques. We demonstrate that myeloid Acly deficiency induces a stable plaque phenotype characterized by increased collagen deposition and fibrous cap thickness, along with a smaller necrotic core. In-depth functional, lipidomic, and transcriptional characterization indicate deregulated fatty acid and cholesterol biosynthesis and reduced liver X receptor activation within the macrophages in vitro. This results in macrophages that are more prone to undergo apoptosis, whilst maintaining their capacity to phagocytose apoptotic cells. Together, our results indicate that targeting macrophage metabolism improves atherosclerosis outcome and we reveal Acly as a promising therapeutic target to stabilize atherosclerotic plaques.

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Section: Discussionmentioning

confidence: 99%

Macrophage ATP citrate lyase deficiency stabilizes atherosclerotic plaques

et al. 2020

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“…In M2 macrophages ACLY is regulated by the Akt-mTORC1 axis, leading to histone acetylation and induction of some M2 genes (87). However, a recent study has shown that polarization of human macrophages toward an M2 phenotype does not require ACLY (88).…”

Section: The Krebs Cyclementioning

confidence: 99%

The Metabolic Signature of Macrophage Responses

et al. 2019

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Macrophages are a heterogeneous population of immune cells playing several and diverse functions in homeostatic and immune responses. The broad spectrum of macrophage functions depends on both heterogeneity and plasticity of these cells, which are highly specialized in sensing the microenvironment and modify their properties accordingly. Although it is clear that macrophage phenotypes are difficult to categorize and should be seen as plastic and adaptable, they can be simplified into two extremes: a pro-inflammatory (M1) and an anti-inflammatory/pro-resolving (M2) profile. Based on this definition, M1 macrophages are able to start and sustain inflammatory responses, secreting pro-inflammatory cytokines, activating endothelial cells, and inducing the recruitment of other immune cells into the inflamed tissue; on the other hand, M2 macrophages promote the resolution of inflammation, phagocytose apoptotic cells, drive collagen deposition, coordinate tissue integrity, and release anti-inflammatory mediators. Dramatic switches in cell metabolism accompany these phenotypic and functional changes of macrophages. In particular, M1 macrophages rely mainly on glycolysis and present two breaks on the TCA cycle that result in accumulation of itaconate (a microbicide compound) and succinate. Excess of succinate leads to Hypoxia Inducible Factor 1α (HIF1α) stabilization that, in turn, activates the transcription of glycolytic genes, thus sustaining the glycolytic metabolism of M1 macrophages. On the contrary, M2 cells are more dependent on oxidative phosphorylation (OXPHOS), their TCA cycle is intact and provides the substrates for the complexes of the electron transport chain (ETC). Moreover, pro- and anti-inflammatory macrophages are characterized by specific pathways that regulate the metabolism of lipids and amino acids and affect their responses. All these metabolic adaptations are functional to support macrophage activities as well as to sustain their polarization in specific contexts. The aim of this review is to discuss recent findings linking macrophage functions and metabolism.

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“…Type 2 cytokines (e.g., IL-4) are involved in M2 macrophage polarization. Response to IL-4 may differ between mouse and human macrophages (19,20). This M1/M2 dichotomy is known to be associated with a distinct arginine metabolism, in particular for mouse macrophages (21,22).…”

Section: Arginine Metabolism a Well-described Pathway Differing Betwmentioning

confidence: 99%