Lactate Inhibits the Pro-Inflammatory Response and Metabolic Reprogramming in Murine Macrophages in a GPR81-Independent Manner

Agustina Errea; Delphine Cayet; Philippe Marchetti; Cong Tang; Jerome Kluza; Stefan Offermanns; Jean-Claude Sirard; Martin Rumbo

doi:10.1371/journal.pone.0163694

Lactate Inhibits the Pro-Inflammatory Response and Metabolic Reprogramming in Murine Macrophages in a GPR81-Independent Manner

PLoS One. 2016 Nov 15;11(11):e0163694. doi: 10.1371/journal.pone.0163694. eCollection 2016.

Authors

Agustina Errea¹, Delphine Cayet², Philippe Marchetti³, Cong Tang⁴, Jerome Kluza³, Stefan Offermanns^{4

5}, Jean-Claude Sirard², Martin Rumbo¹

Affiliations

¹ Instituto de Estudios Inmunológicos y Fisiopatológicos-CONICET- Nacional Universtity of La Plata, 1900, La Plata, Argentina.
² Institut Pasteur de Lille, Inserm, CNRS, Univ. Lille, CHU Lille, U1019-UMR8204-CIIL-Center for Infection and Immunity of Lille, F-59000, Lille, France.
³ Univ. Lille, Inserm, CHU Lille, UMR-S 1172-JPArc-Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer, F-59000, Lille, France.
⁴ Department of Pharmacology, Max Planck Institute for Heart and Lung Research, D-61231, Bad Nauheim, Germany.
⁵ Medical Faculty, J.W. Goethe University, D-60590, Frankfurt, Germany.

Abstract

Lactate is an essential component of carbon metabolism in mammals. Recently, lactate was shown to signal through the G protein coupled receptor 81 (GPR81) and to thus modulate inflammatory processes. This study demonstrates that lactate inhibits pro-inflammatory signaling in a GPR81-independent fashion. While lipopolysaccharide (LPS) triggered expression of IL-6 and IL-12 p40, and CD40 in bone marrow-derived macrophages, lactate was able to abrogate these responses in a dose dependent manner in Gpr81-/- cells as well as in wild type cells. Macrophage activation was impaired when glycolysis was blocked by chemical inhibitors. Remarkably, lactate was found to inhibit LPS-induced glycolysis in wild type as well as in Gpr81-/- cells. In conclusion, our study suggests that lactate can induce GPR81-independent metabolic changes that modulate macrophage pro-inflammatory activation.

MeSH terms

Animals
Bone Marrow Cells / drug effects
Bone Marrow Cells / metabolism
Bone Marrow Cells / pathology
Cellular Reprogramming / drug effects
Extracellular Space / metabolism
Female
Glycolysis / drug effects
Inflammation / metabolism*
Inflammation / pathology
Lactic Acid / pharmacology*
Lipopolysaccharides
Macrophages, Peritoneal / drug effects
Macrophages, Peritoneal / metabolism*
Macrophages, Peritoneal / pathology*
Mice, Inbred C57BL
Receptors, G-Protein-Coupled / metabolism*

Substances

Hcar1 protein, mouse
Lipopolysaccharides
Receptors, G-Protein-Coupled
Lactic Acid

Grants and funding

The work was supported by grants from Agencia Nacional de Promoción Científica y Tecnológica (ANPCYT), INSERM, CNRS, Institut Pasteur de Lille, Université de Lille, CONICET-DAAD and the Argentinian Ministry of Science, Technology and Innovation and the French Ministry for Research and Higher Education (grant ECOS A12B03). AE received a Bernardo Houssay fellowship from CONICET. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.