GPR120 promotes neutrophil control of intestinal bacterial infection

Abstract

G-protein coupled receptor 120 (GPR 120) has been implicated in anti-inflammatory functions. However, how GPR120 regulates the neutrophil function remains unknown. This study investigated the role of GPR120 in the regulation of neutrophil function against enteric bacteria. 16S rRNA sequencing was used for measuring the gut microbiota of wild-type (WT) mice and Gpr120^-/- mice. Citrobacter rodentium infection and dextran sulfate sodium (DSS)-induced colitis models were performed in WT and Gpr120^-/- mice. Mouse peritoneal-derived primary neutrophils were used to determine the neutrophil functions. Gpr120^-/- mice showed altered microbiota composition. Gpr120^-/- mice exhibited less capacity to clear intestinal Citrobacter rodentium and more severe intestinal inflammation upon infection or DSS insults. Depletion of neutrophils decreased the intestinal clearance of Citrobacter rodentium. GPR120 agonist, CpdA, enhanced WT neutrophil production of reactive oxygen species (ROS) and extracellular traps (NETs), and GPR120-deficient neutrophils demonstrated a lower level of ROS and NETs. CpdA-treated neutrophils showed an enhanced capacity to inhibit the growth of Citrobacter rodentium, which was abrogated by the inhibition of either NETs or ROS. CpdA promoted neutrophil inhibition of the growth of commensal bacteria Escherichia coli O9:H4 and pathobiont Escherichia coli O83:H1 isolated from a Crohn's disease patient. Mechanically, mTOR activation and glycolysis mediated GPR120 induction of ROS and NETs in neutrophils. Additionally, CpdA promoted the neutrophil production of IL-17 and IL-22, and treatment with a conditioned medium of GPR120-activated neutrophils increased intestinal epithelial cell barrier functions. Our study demonstrated the critical role of GPR120 in neutrophils in protection against enteric bacterial invasion.

Keywords: GPR120; Interic infection; Intestinal inflammation; Neutrophil; gut microbiota.

Figure 1.

Gpr120^−/− mice demonstrate altered gut microbiota composition.

Figure 2.

Gpr120^−/− mice are impaired in the clearance of intestinal Citrobacter rodentium and are susceptible to intestinal inflammation.

Figure 3.

Depletion of neutrophils decreases the intestinal clearance of Citrobacter rodentium.

Figure 4.

GPR120 agonist promotes neutrophil inhibition of enteric bacterial growth through the upregulation of ROS and NETs.

Figure 5.

mTOR mediates GPR120 induction of neutrophil production of ROS and formation of NETs.

Figure 6.

GPR120 regulates NETs formation in neutrophils through the upregulation of glycolysis.

Figure 7.

GPR120 regulates IL-17A and IL-22 production and IEC barrier function in neutrophils.

Figure 8.

The schematic diagram of GPR120 regulation of neutrophil anti-bacterial function.