G Protein-Coupled Receptor 43 Is Essential for Neutrophil Recruitment during Intestinal Inflammation

Abstract

Molecular danger signals attract neutrophilic granulocytes (polymorphonuclear leukocytes (PMNs)) to sites of infection. The G protein-coupled receptor (GPR) 43 recognizes propionate and butyrate and is abundantly expressed on PMNs. The functional role of GPR43 activation for in vivo orchestration of immune response is unclear. We examined dextrane sodium sulfate (DSS)-induced acute and chronic intestinal inflammatory response in wild-type and Gpr43-deficient mice. The severity of colonic inflammation was assessed by clinical signs, histological scoring, and cytokine production. Chemotaxis of wild-type and Gpr43-deficient PMNs was assessed through transwell cell chemotactic assay. A reduced invasion of PMNs and increased mortality due to septic complications were observed in acute DSS colitis. In chronic DSS colitis, Gpr43−/− animals showed diminished PMN intestinal migration, but protection against inflammatory tissue destruction. No significant difference in PMN migration and cytokine secretion was detected in a sterile inflammatory model. Ex vivo experiments show that GPR43-induced migration is dependent on activation of the protein kinase p38α, and that this signal acts in cooperation with the chemotactic cytokine keratinocyte chemoattractant. Interestingly, shedding of L-selectin in response to propionate and butyrate was compromised in Gpr43−/− mice. These results indicate a critical role for GPR43-mediated recruitment of PMNs in containing intestinal bacterial translocation, yet also emphasize the bipotential role of PMNs in mediating tissue destruction in chronic intestinal inflammation.

Functional interactions between the gut microbiota and host metabolism

“…Signalling through these receptors affects several different functions depending on the cellular type. For example, SCFAs suppress inflammation through GPR43 signalling in immune cells, such as neutrophils 42,43 , and modulate secretion of the hormone GLP-1 -which improves insulin secretion and has antidiabetic effects -by enteroendocrine L-cells in the distal small intestine and colon 44 . In addition, the gut microbiota induces Pyy expression by L-cells through a GPR41-dependent mechanism.…”

Gut microbiota, the pharmabiotics they produce and host health

“…SCFA also regulate gene expression in the host by binding to the G-protein-coupled receptors, GPR41 and GPR43 to impact on several different cellular functions in the host, depending on the cell type (136) . For example, SCFA suppress inflammation through GPR43 signalling in immune cells (137,138) and modulate secretion of the insulin secreting and antidiabetic hormone glucagon-like peptide-1 in the distal small intestine and colon (139) .…”

The Therapeutic Potential of Allosteric Ligands for Free Fatty Acid Sensitive GPCRs

“…FFA2 agonists are reported to inhibit lipolysis and regulate plasma free fatty acid levels [95], enhance glucose uptake in adipocytes [85] and stimulate GLP-1 release [96]; all properties indicating that agonism of FFA2 may be beneficial for metabolic conditions. However, FFA2 agonists, including the allosteric compound 14, also promote neutrophil chemotaxis [93,97], a property potentially detrimental in inflammatory conditions. Indeed, FFA2 -/-mice were protected against tissue damage in a model of colitis [93], suggesting FFA2 antagonists, and not agonists, might be useful therapeutically for inflammation.…”

“…However, FFA2 agonists, including the allosteric compound 14, also promote neutrophil chemotaxis [93,97], a property potentially detrimental in inflammatory conditions. Indeed, FFA2 -/-mice were protected against tissue damage in a model of colitis [93], suggesting FFA2 antagonists, and not agonists, might be useful therapeutically for inflammation. These competing considerations may greatly complicate the development of FFA2 ligands and the receptor as a therapeutic target.…”

“…Although the limited availability of selective ligands has made it challenging to validate FFA2 or FFA3 as therapeutic targets, FFA2 in particular has still attracted significant in- terest for the treatment of metabolic and inflammatory conditions [17,93,94]. FFA2 agonists are reported to inhibit lipolysis and regulate plasma free fatty acid levels [95], enhance glucose uptake in adipocytes [85] and stimulate GLP-1 release [96]; all properties indicating that agonism of FFA2 may be beneficial for metabolic conditions.…”