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

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

doi:10.1016/j.isci.2020.101125

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

iScience. 2020 May 22;23(5):101125. doi: 10.1016/j.isci.2020.101125. Epub 2020 May 4.

Authors

Affiliations

¹ Department of Internal Medicine, Section of Molecular Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
² Department of Internal Medicine, Section of Molecular Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA; Department of Pediatrics, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China.
³ Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
⁴ Department of Internal Medicine, Section on Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
⁵ Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
⁶ Immunity, Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC 27709, USA.
⁷ Department of Internal Medicine, Section of Molecular Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA; Department of Microbiology and Immunology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
⁸ Department of Internal Medicine, Section of Molecular Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA; Department of Microbiology and Immunology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA. Electronic address: xwzhu@wakehealth.edu.

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.

Keywords: Cell Biology; Functional Aspects of Cell Biology; Immunology; Metabolism.

Abstract

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