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Inflammatory monocytes regulate pathologic responses to commensals during acute gastrointestinal infection

Nature Medicine volume 19, pages 713–721 (2013)Cite this article

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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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Figure 1: Collapse of regulatory network and recruitment of inflammatory monocytes during mucosal T. gondii infection.
Figure 2: Ly6Chi inflammatory monocytes have dual features in the SILP.
Figure 3: Ly6Chi inflammatory monocytes acquire regulatory features in response to commensal stimuli.
Figure 4: Impaired Ly6Chi inflammatory monocyte recruitment leads to enhanced neutrophil mediated pathology.
Figure 5: Ly6Chi inflammatory monocytes regulate neutrophil activation through production of PGE2.
Figure 6: PGE2 modulates neutrophil activation in vivo.

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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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Authors and Affiliations

  1. Program in Barrier Immunity and Repair, Mucosal Immunology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, USA

    John R Grainger, Elizabeth A Wohlfert, Nicolas Bouladoux, Michael H Askenase & Yasmine Belkaid

  2. Mucosal Immunity Section, Laboratory of Host Defenses, NIAID, NIH, Bethesda, Maryland, USA

    Ivan J Fuss

  3. Immunology Graduate Group, University of Pennsylvania, Philadelphia, Pennsylvania, USA

    Michael H Askenase

  4. Eosinophil Pathology Unit, Laboratory of Parasitic Diseases, NIAID, NIH, Bethesda, Maryland, USA

    Fanny Legrand

  5. NIAID Biological Imaging Facility, NIAID, NIH, Bethesda, Maryland, USA

    Lily Y Koo

  6. Program in Barrier Immunity and Repair, Laboratory of Molecular Microbiology, NIAID, NIH, Bethesda, Maryland, USA

    Jason M Brenchley

  7. Signaling Systems Unit, Laboratory of Systems Biology, NIAID, NIH, Bethesda, Maryland, USA

    Iain D C Fraser

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  1. John R Grainger
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Contributions

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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Correspondence to Yasmine Belkaid.

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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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