Abstract
The commensal flora can promote both immunity to pathogens and mucosal inflammation. How commensal-driven inflammation is regulated in the context of infection remains poorly understood. Here, we show that during acute mucosal infection of mice with Toxoplasma gondii, inflammatory monocytes acquire a tissue-specific regulatory phenotype associated with production of the lipid mediator prostaglandin E2 (PGE2). Notably, in response to commensals, inflammatory monocytes can directly inhibit neutrophil activation in a PGE2-dependent manner. Further, in the absence of inflammatory monocytes, mice develop severe neutrophil-mediated pathology in response to pathogen challenge that can be controlled by PGE2 analog treatment. Complementing these findings, inhibition of PGE2 led to enhanced neutrophil activation and host mortality after infection. These data demonstrate a previously unappreciated dual action of inflammatory monocytes in controlling pathogen expansion while limiting commensal-mediated damage to the gut. Collectively, our results place inflammatory monocyte–derived PGE2 at the center of a commensal-driven regulatory loop required to control host-commensal dialog during pathogen-induced inflammation.
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Acknowledgements
This work was supported by the Division of Intramural Research, NIAID. We thank members of the Belkaid lab for thoughtful discussion and critical reading of the manuscript, K. Holmes, E. Stregevsky and the NIAID Sorting Facility, K. Beacht and J. Konkel for technical assistance, C. Brown for assistance with tissue staining, O. Schwartz and the NIAID Biological Imaging Facility for assistance with confocal microscopy, T. Meyers and the NIAID Genomic Technologies Section for microarray processing, J. Skinner and the NIAID Bioinformatics and Computational Bioscience Branch for assistance with microarray analysis and L. Hooper and the University of Texas Southwestern Medical Center for sharing protocols. ME-49 clone C1 of T. gondii was provided by M.E. Grigg, NIAID, NIH.
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J.R.G., E.A.W., M.H.A., N.B., F.L. and Y.B. designed and performed experiments. J.R.G., E.A.W., M.H.A., I.D.C.F., I.J.F., L.Y.K. and Y.B. analyzed the data. J.R.G., N.B. and Y.B. wrote the manuscript.
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Grainger, J., Wohlfert, E., Fuss, I. et al. Inflammatory monocytes regulate pathologic responses to commensals during acute gastrointestinal infection. Nat Med 19, 713–721 (2013). https://doi.org/10.1038/nm.3189
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DOI: https://doi.org/10.1038/nm.3189
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