Volume 146, Issue 7, Pages 1602-1605 (June 2014) The Anti-inflammasome Effect of Lactate and the Lactate GPR81-Receptor in Pancreatic and Liver Inflammation  Markus M. Lerch  Gastroenterology  Volume 146, Issue 7, Pages 1602-1605 (June 2014) DOI: 10.1053/j.gastro.2014.04.025 Copyright © 2014 AGA Institute Terms and Conditions

Figure 1 Blockage of NLRP3 inflammasome activation via Gi protein-coupled receptor 81 (GPR81). Inflammasomes are key signaling platforms for the detection of pathogenic microorganisms and sterile stressors leading to activation of the highly pro-inflammatory cytokine interleukin (IL)-1β. Activation of the canonical NLRP3 inflammasome has been proposed to act according to a 2-checkpoint model of priming and activation. Initially, an activating signal transmitted via pattern recognition receptor (PRR) on the cell surface results in NLRP3 up-regulation as a priming reaction. Thereafter Toll-like receptor (TLR)-4 is activated by lipopolysaccharide, which leads to activation of TRIF and binding of NLRP3 to ASC. Subsequently, pro–IL-β1 expression is up-regulated and activated via caspase 1. There are several other stimuli involved in the activation of NLRP3, such as bacterial membrane components, cathepsin B release from lysosomes, low potassium levels, high calcium levels, or reactive oxygen species (ROS) release from mitochondria; those stimuli and their respective mechanisms have not been addressed in the present study. The specific ligand of the plasma membrane GPR81, a 7-transmembrane receptor, is lactate. Binding of lactate recruits the intracellular adaptor molecule ARRB2 to the receptor and subsequent inhibition of the NLRP3 inflammasome with a reduction of the IL-β–mediated pro-inflammatory response. NF-κB, nuclear factor-κB. Gastroenterology 2014 146, 1602-1605DOI: (10.1053/j.gastro.2014.04.025) Copyright © 2014 AGA Institute Terms and Conditions