Activation of GPR37 in macrophages confers protection against infection-induced sepsis and pain-like behaviour in mice

Sangsu Bang, Christopher R. Donnelly, Xin Luo, Maria Toro-Moreno, Xueshu Tao, Zilong Wang, Sharat Chandra, Andrey V. Bortsov, Emily R. Derbyshire and Ru-Rong Ji ()
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Sangsu Bang: Duke University Medical Center
Christopher R. Donnelly: Duke University Medical Center
Xin Luo: Duke University Medical Center
Maria Toro-Moreno: Duke University
Xueshu Tao: Duke University Medical Center
Zilong Wang: Duke University Medical Center
Sharat Chandra: Duke University Medical Center
Andrey V. Bortsov: Duke University Medical Center
Emily R. Derbyshire: Duke University
Ru-Rong Ji: Duke University Medical Center

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: Abstract GPR37 was discovered more than two decades ago, but its biological functions remain poorly understood. Here we report a protective role of GPR37 in multiple models of infection and sepsis. Mice lacking Gpr37 exhibited increased death and/or hypothermia following challenge by lipopolysaccharide (LPS), Listeria bacteria, and the mouse malaria parasite Plasmodium berghei. Sepsis induced by LPS and Listeria in wild-type mice is protected by artesunate (ARU) and neuroprotectin D1 (NPD1), but the protective actions of these agents are lost in Gpr37−/− mice. Notably, we found that ARU binds to GPR37 in macrophages and promotes phagocytosis and clearance of pathogens. Moreover, ablation of macrophages potentiated infection, sepsis, and their sequelae, whereas adoptive transfer of NPD1- or ARU-primed macrophages reduced infection, sepsis, and pain-like behaviors. Our findings reveal physiological actions of ARU in host cells by activating macrophages and suggest that GPR37 agonists may help to treat sepsis, bacterial infections, and malaria.

Date: 2021
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DOI: 10.1038/s41467-021-21940-8

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