https://orcid.org/0000-0003-4167-7395
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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.
Abbreviations
| CFU | = | colony-forming units |
| DPI | = | Diphenyleneiodonium |
| ECAR | = | Extracellular Acidification Rate |
| GPR120 | = | G-protein coupled receptor 120 |
| NETs | = | neutrophil extracellular traps |
| OCR | = | Oxygen Consumption Rate |
| PPP | = | pentose phosphate pathway |
| PUFA | = | polyunsaturated fatty acids |
| ROS | = | reactive oxygen species |
| WT | = | wild-type |
| 2DG | = | 2-Deoxy-D-glucose. |
Acknowledgments
We appreciate Dr. Sherry Haller of the University of Texas Medical Branch for proofreading the manuscript. was created with Biorender.com.
Disclosure statement
No potential conflict of interest was reported by the authors.
Supplementary material
Supplemental data for this article can be accessed online at https://doi.org/10.1080/19490976.2023.2190311.
Data availability statement
16S rRNA sequencing data have been deposited in SRA under the BioProject number PRJNA716350 (https://www.ncbi.nlm.nih.gov/bioproject/PRJNA716350).
Author contributions
Conceptualization: W.Y., and Y.C.; Methodology: Z.Z., W.Y., G.G., and Y.C.; Investigation: Z.Z., W.Y., T.Y., Y.Y. (Yu Yu), X.Z., Y.Y. (Yanbo Yu), C.G., A.J.B., S.Y., G.G., and Y.C.; Resources: Q.Z., M.L.; Writing – original draft preparation: Z.Z., W.Y., and Y.C.; Writing – review and editing: W.Y., and Y.C. with input from all other authors; Supervision: Y.C.; Funding acquisition: Y.C.
Correction Statement
This article was originally published with errors, which have now been corrected in the online version. Please see Correction (http://dx.doi.org/10.1080/19490976.2024.2329383)