SREBP1-induced fatty acid synthesis depletes macrophages antioxidant defences to promote their alternative activation

Bidault, Guillaume; Virtue, Samuel; Petkevicius, Kasparas; Jolin, Helen E.; Dugourd, Aurélien; Guénantin, Anne-Claire; Leggat, Jennifer; Mahler–Araujo, Betania; Lam, Brian; Marcella, Kenneth L.; Dale, Martin; Carobbio, Stefania; Kaser, Arthur; Fallon, Padraic G.; Sáez-Rodríguez, Julio; McKenzie, Andrew N. J.; Vidal-Puig, António

doi:10.1038/s42255-021-00440-5

Cited by 37 publications

(27 citation statements)

References 74 publications

(103 reference statements)

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“…Specifically, IL-4 induces de novo adipogenesis by activating the transcription of sterol regulatory element-binding protein 1. During the process of lipogenesis, a large amount of NADPH is consumed, and the levels of reactive oxygen species are elevated, which acts as a secondary messenger to signal adequate de novo lipogenesis and promote alternative polarization of macrophages [ 88 ].…”

Section: Regulatory Mechanisms Of Macrophage Polarization In Adipose ...mentioning

confidence: 99%

Adipose tissue macrophages: implications for obesity-associated cancer

Sun

et al. 2023

Military Med Res

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Obesity is one of the most serious global health problems, with an incidence that increases yearly and coincides with the development of cancer. Adipose tissue macrophages (ATMs) are particularly important in this context and contribute to linking obesity-related inflammation and tumor progression. However, the functions of ATMs on the progression of obesity-associated cancer remain unclear. In this review, we describe the origins, phenotypes, and functions of ATMs. Subsequently, we summarize the potential mechanisms on the reprogramming of ATMs in the obesity-associated microenvironment, including the direct exchange of dysfunctional metabolites, inordinate cytokines and other signaling mediators, transfer of extracellular vesicle cargo, and variations in the gut microbiota and its metabolites. A better understanding of the properties and functions of ATMs under conditions of obesity will lead to the development of new therapeutic interventions for obesity-related cancer.

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Section: Regulatory Mechanisms Of Macrophage Polarization In Adipose ...mentioning

confidence: 99%

Adipose tissue macrophages: implications for obesity-associated cancer

Sun

et al. 2023

Military Med Res

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“…The thymus is an immunetolerant microenvironment that has abundant expression of the type 2 cytokine IL-4 (Miller et al, 2018). It is also plausible that, to maintain the alternatively activated state of TM4s, the SREBP-1-mediated de novo lipogenesis consumes NADPH (Bidault et al, 2021), which contributes to the rise of ROS levels. Another possible scenario for ROS elevation upon efferocytosis is the need for LC3-associated phagocytosis (LAP) to process the engulfed dying cells (Boada-Romero et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Multiomics reveal the central role of pentose phosphate pathway in resident thymic macrophages to cope with efferocytosis-associated stress

et al. 2022

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“…4,10 There is now evidence to support a role for both exogenous FA uptake, 11,12 as well as de novo lipogenesis in M[IL-4]. 51 Despite the potentially divergent sources of FA, differences in the side chain composition of choline-containing phospholipids between macrophage polarizations may fuel distinct lipid signaling pathways following phospholipase-specific processing.…”

Section: Discussionmentioning

confidence: 99%

Choline metabolism underpins macrophage IL-4 polarization and RELMα up-regulation in helminth infection

Ghorbani

Kim

Smith

et al. 2022

Preprint

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Choline is an essential nutrient and in macrophages, mainly supports phosphatidylcholine (PC) synthesis. Cellular uptake and incorporation of choline into PC is critical for LPS-induced macrophage inflammation. Here, we examined choline metabolism in the context of IL-4 polarization of mouse macrophages in vitro and in vivo. Like LPS, IL-4 increased the levels of choline transporter-like protein 1, the rate of choline uptake, and incorporation into PC. Targeted lipidomics analysis revealed higher PC content in IL-4-polarized macrophages, with enrichment in low-saturated species. Pharmacological inhibition of choline metabolism significantly suppressed the transcription of certain hallmark IL-4 genes (Retnla) but not others (Chil3, Mrc1, Arg1). Blocking choline metabolism diminished the expression and secretion of RELMα protein (encoded by Retnla), while also limiting PD-L2 up-regulation and increasing PD-L1 expression. In vivo administration of RSM-932a, a choline kinase inhibitor, caused a dramatic shift in the peritoneal immune cell profile and up-regulated macrophage CD86 and PD-L1, while down-regulating CD206 and PD-L2. Strikingly, blocking choline metabolism lowered RELMα expression in multiple cell-types and tissues in naive mice as well as mice infected with the helminth pathogens Heligmosomoides polygyrus and Nippostrongylus brasiliensis. There were no changes in pathogen burden or clearance in the two separate helminth models. In contrast, in dextran sulfate sodium-induced colitis, loss of colon length as a marker of inflammation was mitigated by choline metabolism inhibition. These data demonstrate a critical link between choline and macrophage effector functions and suggest that targeting choline metabolism could be leveraged to fine-tune immunopathology.

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SREBP1-induced fatty acid synthesis depletes macrophages antioxidant defences to promote their alternative activation

Cited by 37 publications

References 74 publications

Adipose tissue macrophages: implications for obesity-associated cancer

Adipose tissue macrophages: implications for obesity-associated cancer

Multiomics reveal the central role of pentose phosphate pathway in resident thymic macrophages to cope with efferocytosis-associated stress

Choline metabolism underpins macrophage IL-4 polarization and RELMα up-regulation in helminth infection

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