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Nociceptor sensory neurons suppress neutrophil and γδ T cell responses in bacterial lung infections and lethal pneumonia

Nature Medicine volume 24, pages 417–426 (2018)Cite this article

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Abstract

Lung-innervating nociceptor sensory neurons detect noxious or harmful stimuli and consequently protect organisms by mediating coughing, pain, and bronchoconstriction. However, the role of sensory neurons in pulmonary host defense is unclear. Here, we found that TRPV1+ nociceptors suppressed protective immunity against lethal Staphylococcus aureus pneumonia. Targeted TRPV1+-neuron ablation increased survival, cytokine induction, and lung bacterial clearance. Nociceptors suppressed the recruitment and surveillance of neutrophils, and altered lung γδ T cell numbers, which are necessary for immunity. Vagal ganglia TRPV1+ afferents mediated immunosuppression through release of the neuropeptide calcitonin gene–related peptide (CGRP). Targeting neuroimmunological signaling may be an effective approach to treat lung infections and bacterial pneumonia.

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Figure 1: TRPV1 neurons regulate survival and the outcome of lethal S. aureus pneumonia.
Figure 2: TRPV1 neurons suppress lung inflammation and cytokine induction during S. aureus infection.
Figure 3: TRPV1 neurons suppress recruitment of Ly6G+ neutrophils essential for host defense against lethal pneumonia.
Figure 4: Neutrophil dynamics are altered in TRPV1-neuron-ablated mice.
Figure 5: TRPV1 neurons regulate lung γδ T cells, which mediate host protection against S. aureus pneumonia.
Figure 6: Vagal TRPV1 neurons and the neuropeptide CGRP regulate S. aureus pneumonia.

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Change history

  • 16 July 2018

    In the version of this article initially published, the line graph showing TNF-α levels in Fig. 2d was inadvertently duplicated. A graph of IL-6 levels should be shown in place of the duplication. These results were also incorrectly described in the main text, which originally stated: "At an early time point of infection (6 h), RTX-treated mice showed higher induction of total inflammatory-protein levels in the bronchoalveolar lavage fluid (BALF) (Fig. 2c), as well as levels of the cytokines TNF-α and IL-6, and the chemokine CXCL-1 (Fig. 2d)". This should instead read: "At an early time point of infection (6 h), RTX-treated mice showed higher induction of total inflammatory-protein levels in the bronchoalveolar lavage fluid (BALF) (Fig. 2c), as well as levels of the cytokine TNF-α and the chemokine CXCL-1 (Fig. 2d)". In the supplementary information initially posted online, incorrect bar graphs were presented in Supplementary Fig. 1b (VG, TRPV1+ data, top panel) and Supplementary Fig. 4b (DRG, CGRP+ data, middle panel). The errors have been corrected in the HTML and PDF versions of this article.

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Acknowledgements

We thank K. Blake and N. Lai for technical assistance, and J. Bubeck Wardenburg and C. Altier for helpful discussions. We thank M. Hoon (NIH) for Trpv1-Dtr mice, C. Benoist (Harvard Medical School) and A. Mann (Harvard Medical School) for Tcrd−/− mice, G. Pier (Brigham and Women's Hospital) and M. Gadjeva (Brigham and Women's Hospital) for P. aeruginosa, R. Malley (Boston Children's Hospital) for S. pneumoniae, and M. Otto (NIH) for S. aureus bacterial strains. This work was supported by National Institutes of Health (NIH) grants DP2AT009499 (I.M.C.), K22AI114810 (I.M.C.), R01AI130019 (I.M.C.), 1KO8AI123516 (P.R.B.), and R01HL132255 (S.D.L.); an HHMI Faculty Scholars Award (S.D.L.); NIH 5F31HL132645 (B.D.U.); and Canadian Institutes of Health Research (CIHR) grant RS-342013 (B.G.Y.).

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Authors and Affiliations

  1. Department of Microbiology and Immunobiology, Division of Immunology, Harvard Medical School, Boston, Massachusetts, USA

    Pankaj Baral, Meghna Bist, Talia Kirschbaum, Yibing Wei, Yan Zhou & Isaac M Chiu

  2. Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA

    Benjamin D Umans & Stephen D Liberles

  3. Department of Critical Care, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada

    Lu Li & Bryan G Yipp

  4. Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts, USA

    Antonia Wallrapp & Vijay K Kuchroo

  5. Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA

    Patrick R Burkett

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Contributions

P.B. and I.M.C. conceived the study. P.B., B.D.U., L.L., B.G.Y., A.W., P.R.B., V.K.K., S.D.L., and I.M.C. designed experiments, analyzed data, and interpreted results. P.B. performed animal infections, survival analysis, bacterial-load recovery, cytokine measurements, FACS, CGRP assays, and neutrophil killing experiments; B.D.U. performed VG injections and immunostaining; A.W. and P.R.B. performed purification of lung cells and quantitative PCR experiments; M.B. performed lung immunostaining and quantification; T.K. and Y.W. performed cytokine measurements and histology; Y.Z. performed neuronal cultures and CGRP assays; L.L. and B.G.Y. performed animal infections with in vivo intravital microscopy of neutrophil movement and migration. P.B. and I.M.C. wrote the manuscript, which was edited by S.D.L., B.G.Y., B.D.U., P.B. and I.M.C.

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Correspondence to Isaac M Chiu.

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P.B. and I.M.C. are co-inventors on a patent application filed by Harvard incorporating discoveries described in the manuscript.

Supplementary information

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Supplementary Figures 1–33 (PDF 13453 kb)

Life Sciences Reporting Summary (PDF 288 kb)

Neutrophil dynamic behaviors revealed using pulmonary intravital microscopy

Mice were pretreated with either vehicle control or RTX 4 weeks prior to GFP-S. aureus (green) pneumonia. Animals received 1x108 CFU into the lung and intravital imaging was performed at 4 hours post-infection. Neutrophils were visualized using fluorescently conjugated anti-Ly6G antibodies (red) and the endothelium was visualized using fluorescently conjugated anti-CD31 antibodies given intravenously prior to imaging. Representative video recordings of experiments from vehicle control and RTX-treated mice are shown side by side for comparison and then individually. Imaging experiments were repeated 3 separate times for vehicle control and 4 times for RTX. (MOV 816 kb)

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Baral, P., Umans, B., Li, L. et al. Nociceptor sensory neurons suppress neutrophil and γδ T cell responses in bacterial lung infections and lethal pneumonia. Nat Med 24, 417–426 (2018). https://doi.org/10.1038/nm.4501

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