Journal
GASTROENTEROLOGY
Volume 146, Issue 7, Pages 1763-1774Publisher
W B SAUNDERS CO-ELSEVIER INC
DOI: 10.1053/j.gastro.2014.03.014
Keywords
Innate Immune Response; Pancreas; Immune Regulation; Mouse Model
Categories
Funding
- National Institutes of Health [R01DK076674-01A2, 5U01AA021912-02, K08DK092281, DK54021, P30DK34989]
- VA Merit awards
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BACKGROUND & AIMS: The NACHT, LRR, and pyrin domain-containing protein 3 (NLRP3) inflammasome induces inflammation in response to organ injury, but little is known about its regulation. Toll-like receptors (TLRs) provide the first signal required for activation of the inflammasome and stimulate aerobic glycolysis to generate lactate. We examined whether lactate and the lactate receptor, G(i)-protein-coupled receptor 81 (GPR81), regulate TLR induction of signal 1 and limit inflammasome activation and organ injury. METHODS: Primary mouse macrophages and human monocytes were incubated with TLR4 agonists and lactate and assayed for levels of pro-interleukin (IL)1 beta, NLRP3, and caspase-1 (CASP1); release of IL1 beta; and activation of nuclear factor-kappa B (NF-kappa B) and caspase-1. Small interfering RNAs were used to reduce levels of GPR81 and arrestin beta-2 (ARRB2), and an NF-kappa B luciferase reporter transgene was transfected in RAW 264.7 cells. Cell lysates were analyzed by immunoprecipitation with an antibody against GPR81. Acute hepatitis was induced in C56BL/6N mice by administration of lipopolysaccharide and D-galactosamine. Acute pancreatitis was induced by administration of lipopolysaccharide and cerulein. Some mice were given intraperitoneal injections of sodium lactate or small interfering RNA against Gpr81. Activation of NF-kappa B in tissue macrophages was assessed in mice that expressed a reporter transgene. RESULTS: In macrophages and monocytes, increasing concentrations of lactate reduced TLR4-mediated induction of Il1B, Nlrp3, and Casp1; activation of NF-kappa B; release of IL1 beta; and cleavage of CASP1. GPR81 and ARRB2 physically interacted and were required for these effects. The administration of lactate reduced inflammation and organ injury in mice with immune hepatitis; this reduction required Gpr81 dependence in vivo. Lactate also prevented activation of NF-kappa B in macrophages of mice, and, when given after injury, reduced the severity of acute pancreatitis and acute liver injury. CONCLUSIONS: Lactate negatively regulates TLR induction of the NLRP3 inflammasome and production of IL1 beta, via ARRB2 and GPR81. Lactate could be a promising immunomodulatory therapy for patients with acute organ injury.
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