Solute Carrier Family 37 Member 2 (SLC37A2) Negatively Regulates Murine Macrophage Inflammation by Controlling Glycolysis

Overview

Journal iScience

Publisher Cell Press

Date 2020 May 20

PMID 32428862

Citations 9

Authors

Zhan Wang

Qingxia Zhao

Yan Nie

Yi Yu

Biswapriya B Misra

Manal Zabalawi

Jeff W Chou

Chia-Chi C Key

Anthony J Molina

Matthew A Quinn

Michael B Fessler

John S Parks

Charles E McCall

Xuewei Zhu

Affiliations

Soon will be listed here.

Abstract

Increased flux of glucose through glycolysis is a hallmark of inflammatory macrophages and is essential for optimal effector functions. Solute carrier (SLC) 37A2 is an endoplasmic reticulum-anchored phosphate-linked glucose-6-phosphate transporter that is highly expressed in macrophages and neutrophils. We demonstrate that SLC37A2 plays a pivotal role in murine macrophage inflammatory activation and cellular metabolic rewiring. Toll-like receptor (TLR) 4 stimulation by lipopolysaccharide (LPS) rapidly increases macrophage SLC37A2 protein expression. SLC37A2 deletion reprograms macrophages to a hyper-glycolytic process and accelerates LPS-induced inflammatory cytokine production, which partially depends on nicotinamide adenine dinucleotide (NAD) biosynthesis. Blockade of glycolysis normalizes the differential expression of pro-inflammatory cytokines between control and SLC37A2 deficient macrophages. Conversely, overexpression of SLC37A2 lowers macrophage glycolysis and significantly reduces LPS-induced pro-inflammatory cytokine expression. In conclusion, our study suggests that SLC37A2 dampens murine macrophage inflammation by down-regulating glycolytic reprogramming as a part of macrophage negative feedback system to curtail acute innate activation.

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References

Kim S, Jun H, Mead P, Mansfield B, Chou J . Neutrophil stress and apoptosis underlie myeloid dysfunction in glycogen storage disease type Ib. Blood. 2008; 111(12):5704-11. PMC: 2424162. DOI: 10.1182/blood-2007-12-129114. View

Murphy M, ONeill L . Krebs Cycle Reimagined: The Emerging Roles of Succinate and Itaconate as Signal Transducers. Cell. 2018; 174(4):780-784. DOI: 10.1016/j.cell.2018.07.030. View

Tannahill G, Curtis A, Adamik J, Palsson-McDermott E, McGettrick A, Goel G . Succinate is an inflammatory signal that induces IL-1β through HIF-1α. Nature. 2013; 496(7444):238-42. PMC: 4031686. DOI: 10.1038/nature11986. View

Kawai T, Akira S . The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol. 2010; 11(5):373-84. DOI: 10.1038/ni.1863. View

Traves P, de Atauri P, Marin S, Pimentel-Santillana M, Rodriguez-Prados J, Marin de Mas I . Relevance of the MEK/ERK signaling pathway in the metabolism of activated macrophages: a metabolomic approach. J Immunol. 2011; 188(3):1402-10. DOI: 10.4049/jimmunol.1101781. View

Huh S, Song H, Jeong G, Jang H, Seo N, Lee J . Suppression of the ERK-SRF axis facilitates somatic cell reprogramming. Exp Mol Med. 2018; 50(2):e448. PMC: 5903827. DOI: 10.1038/emm.2017.279. View

Vadlakonda L, Dash A, Pasupuleti M, Anil Kumar K, Reddanna P . The Paradox of Akt-mTOR Interactions. Front Oncol. 2013; 3:165. PMC: 3687210. DOI: 10.3389/fonc.2013.00165. View

Minhas P, Liu L, Moon P, Joshi A, Dove C, Mhatre S . Macrophage de novo NAD synthesis specifies immune function in aging and inflammation. Nat Immunol. 2018; 20(1):50-63. PMC: 6768398. DOI: 10.1038/s41590-018-0255-3. View

Langston P, Nambu A, Jung J, Shibata M, Aksoylar H, Lei J . Glycerol phosphate shuttle enzyme GPD2 regulates macrophage inflammatory responses. Nat Immunol. 2019; 20(9):1186-1195. PMC: 6707851. DOI: 10.1038/s41590-019-0453-7. View

10.

Haschemi A, Kosma P, Gille L, Evans C, Burant C, Starkl P . The sedoheptulose kinase CARKL directs macrophage polarization through control of glucose metabolism. Cell Metab. 2012; 15(6):813-26. PMC: 3370649. DOI: 10.1016/j.cmet.2012.04.023. View

11.

Perrin-Cocon L, Aublin-Gex A, Diaz O, Ramiere C, Peri F, Andre P . Toll-like Receptor 4-Induced Glycolytic Burst in Human Monocyte-Derived Dendritic Cells Results from p38-Dependent Stabilization of HIF-1α and Increased Hexokinase II Expression. J Immunol. 2018; 201(5):1510-1521. DOI: 10.4049/jimmunol.1701522. View

12.

Nishizawa T, Kanter J, Kramer F, Barnhart S, Shen X, Vivekanandan-Giri A . Testing the role of myeloid cell glucose flux in inflammation and atherosclerosis. Cell Rep. 2014; 7(2):356-365. PMC: 4021396. DOI: 10.1016/j.celrep.2014.03.028. View

13.

Jha A, Huang S, Sergushichev A, Lampropoulou V, Ivanova Y, Loginicheva E . Network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization. Immunity. 2015; 42(3):419-30. DOI: 10.1016/j.immuni.2015.02.005. View

14.

Bourgin-Hierle C, Gobert-Gosse S, Therier J, Grasset M, Mouchiroud G . Src-family kinases play an essential role in differentiation signaling downstream of macrophage colony-stimulating factor receptors mediating persistent phosphorylation of phospholipase C-gamma2 and MAP kinases ERK1 and ERK2. Leukemia. 2007; 22(1):161-9. DOI: 10.1038/sj.leu.2404986. View

15.

Freemerman A, Johnson A, Sacks G, Milner J, Kirk E, Troester M . Metabolic reprogramming of macrophages: glucose transporter 1 (GLUT1)-mediated glucose metabolism drives a proinflammatory phenotype. J Biol Chem. 2014; 289(11):7884-96. PMC: 3953299. DOI: 10.1074/jbc.M113.522037. View

16.

Freemerman A, Zhao L, Pingili A, Teng B, Cozzo A, Fuller A . Myeloid -Deficient Murine Model Revealed Macrophage Activation and Metabolic Phenotype Are Fueled by GLUT1. J Immunol. 2019; 202(4):1265-1286. PMC: 6360258. DOI: 10.4049/jimmunol.1800002. View

17.

Chen L, Shieh J, Lin B, Pan C, Gao J, Murphy P . Impaired glucose homeostasis, neutrophil trafficking and function in mice lacking the glucose-6-phosphate transporter. Hum Mol Genet. 2003; 12(19):2547-58. DOI: 10.1093/hmg/ddg263. View

18.

Lee J, Liu R, Li J, Zhang C, Wang Y, Cai Q . Stabilization of phosphofructokinase 1 platelet isoform by AKT promotes tumorigenesis. Nat Commun. 2017; 8(1):949. PMC: 5643558. DOI: 10.1038/s41467-017-00906-9. View

19.

Pearce E, Pearce E . Metabolic pathways in immune cell activation and quiescence. Immunity. 2013; 38(4):633-43. PMC: 3654249. DOI: 10.1016/j.immuni.2013.04.005. View

20.

Jun H, Weinstein D, Lee Y, Mansfield B, Chou J . Molecular mechanisms of neutrophil dysfunction in glycogen storage disease type Ib. Blood. 2014; 123(18):2843-53. PMC: 4007611. DOI: 10.1182/blood-2013-05-502435. View