Letter | Published:

Sessile alveolar macrophages communicate with alveolar epithelium to modulate immunity

Nature volume 506, pages 503506 (27 February 2014) | Download Citation

Abstract

The tissue-resident macrophages of barrier organs constitute the first line of defence against pathogens at the systemic interface with the ambient environment. In the lung, resident alveolar macrophages (AMs) provide a sentinel function against inhaled pathogens1. Bacterial constituents ligate Toll-like receptors (TLRs) on AMs2, causing AMs to secrete proinflammatory cytokines3 that activate alveolar epithelial receptors4, leading to recruitment of neutrophils that engulf pathogens5,6. Because the AM-induced response could itself cause tissue injury, it is unclear how AMs modulate the response to prevent injury. Here, using real-time alveolar imaging in situ, we show that a subset of AMs attached to the alveolar wall form connexin 43 (Cx43)-containing gap junction channels with the epithelium. During lipopolysaccharide-induced inflammation, the AMs remained sessile and attached to the alveoli, and they established intercommunication through synchronized Ca2+ waves, using the epithelium as the conducting pathway. The intercommunication was immunosuppressive, involving Ca2+-dependent activation of Akt, because AM-specific knockout of Cx43 enhanced alveolar neutrophil recruitment and secretion of proinflammatory cytokines in the bronchoalveolar lavage. A picture emerges of a novel immunomodulatory process in which a subset of alveolus-attached AMs intercommunicates immunosuppressive signals to reduce endotoxin-induced lung inflammation.

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Acknowledgements

We thank B. Reizis for providing the Cd11c-cre mice and J. Whitsett for providing the Spc-cre mice. We thank I. Tabas for discussions. This study was supported by US National Institutes of Health grants HL78645, HL57556 and HL64896 to J.B., HL73989 to A.S.P., and Parker B. Francis Fellowships to T.S.C. and M.N.I.

Author information

Affiliations

  1. Lung Biology Laboratory, Department of Medicine, Division of Pulmonary, Allergy and Critical Care, Columbia University Medical Center, New York, New York 10032, USA

    • Kristin Westphalen
    • , Galina A. Gusarova
    • , Mohammad N. Islam
    •  & Jahar Bhattacharya
  2. Department of Medicine, Division of Molecular Medicine, Columbia University Medical Center, New York, New York 10032, USA

    • Manikandan Subramanian
  3. Department of Pediatrics, Columbia University Medical Center, New York, New York 10032, USA

    • Taylor S. Cohen
    •  & Alice S. Prince
  4. Department of Physiology & Cellular Biophysics, College of Physicians and Surgeons, Columbia University Medical Center, New York, New York 10032, USA

    • Jahar Bhattacharya

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Contributions

K.W. designed and carried out the experiments, prepared the figures and wrote the initial manuscript. G.A.G. contributed to western blot, immunoprecipitation and FRAP experiments. M.N.I. carried out the NF-κB in situ stainings, and contributed to BAL cell counting and survival studies. M.S. performed the antigen-presentation assay and provided the CD11c Myd88−/− mice. T.S.C. provided S. aureus and contributed to ELISA studies. A.S.P. contributed to the experimental design. J.B. was responsible for the overall project, designed the experiments and wrote the initial manuscript. All authors edited the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Jahar Bhattacharya.

Extended data

Supplementary information

PDF files

  1. 1.

    Supplementary Figures

    This file contains Supplementary Figure 1, which contains the alveolar markings for Supplementary Video 1.

Videos

  1. 1.

    Leukocyte movement in the alveolar airspace.

    This movie file contains a 10-min imaging sequence from alveoli shown in Supplementary Figure 1. It depicts intra-alveolar leukocyte motility after LPS challenge.

  2. 2.

    Intercommunication of AM Ca2+ spikes.

    This file contains shows additional information for figure 2b in the main paper. The movie montage shows Ca2+ spikes (fluorescence increases) in AMs that travel from left to right.

About this article

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DOI

https://doi.org/10.1038/nature12902

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