Letter | Published:

Macrophages redirect phagocytosis by non-professional phagocytes and influence inflammation

Nature volume 539, pages 570574 (24 November 2016) | Download Citation

Abstract

Professional phagocytes (such as macrophages1) and non-professional phagocytes2,3,4,5,6,7,8 (such as epithelial cells) clear billions of apoptotic cells and particles on a daily basis9. Although professional and non-professional macrophages reside in proximity in most tissues, whether they communicate with each other during cell clearance, and how this might affect inflammation, is not known10. Here we show that macrophages, through the release of a soluble growth factor and microvesicles, alter the type of particles engulfed by non-professional phagocytes and influence their inflammatory response. During phagocytosis of apoptotic cells or in response to inflammation-associated cytokines, macrophages released insulin-like growth factor 1 (IGF-1). The binding of IGF-1 to its receptor on non-professional phagocytes redirected their phagocytosis, such that uptake of larger apoptotic cells was reduced whereas engulfment of microvesicles was increased. IGF-1 did not alter engulfment by macrophages. Macrophages also released microvesicles, whose uptake by epithelial cells was enhanced by IGF-1 and led to decreased inflammatory responses by epithelial cells. Consistent with these observations, deletion of IGF-1 receptor in airway epithelial cells led to exacerbated lung inflammation after allergen exposure. These genetic and functional studies reveal that IGF-1- and microvesicle-dependent communication between macrophages and epithelial cells can critically influence the magnitude of tissue inflammation in vivo.

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Acknowledgements

The authors thank members of the Ravichandran laboratory for discussions and critical reading of manuscript; S. Arandjelovic, K. Penberthy, and L. Haney for scoring histology slides, and J. Perry for assistance with generation of the heat map, and the UVa Flow Cytometry Core and the UVa Molecular Electron Microscopy Core. This work is supported by grants to K.S.R. from the NIGMS (GM064709), NIMH (MH096484), NHLBI (P01HL120840), and Center for Cell Signalling at the University of Virginia, NHLBI (HL132287 and HL091127) to Y.M.S. and K23 HL12610 to U.E. Additional support was provided via the NIH Training Grants T32 GM008136 (Cell and Molecular Biology) to C.Z.H.; T32 AI007496 (Immunology) to C.Z.H., M.W.B., and I.J.J.; and T32 GM007267 (MSTP) to M.W.B.

Author information

Affiliations

  1. The Center for Cell Clearance, University of Virginia, Charlottesville, Virginia 22903, USA

    • Claudia Z. Han
    • , Ignacio J. Juncadella
    • , Jason M. Kinchen
    • , Monica W. Buckley
    •  & Kodi S. Ravichandran
  2. Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, Virginia 22903, USA

    • Claudia Z. Han
    • , Monica W. Buckley
    •  & Kodi S. Ravichandran
  3. Department of Medicine, University of Virginia, Charlottesville, Virginia 22903, USA

    • Alexander L. Klibanov
    • , Yun M. Shim
    •  & Kenneth S. Tung
  4. Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia 22903, USA

    • Alexander L. Klibanov
  5. Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, Virginia 22903, USA

    • Kelly Dryden
  6. Department of Medicine, Division of Endocrinology and Metabolism, University of Virginia, Charlottesville, Virginia 22903, USA

    • Suna Onengut-Gumuscu
  7. Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia 22903, USA

    • Suna Onengut-Gumuscu
  8. Department of Medicine, Division of Nephrology, University of Virginia, Charlottesville, Virginia 22903, USA

    • Uta Erdbrügger
  9. Department of Public Health Sciences, University of Virginia, Charlottesville, Virginia 22903, USA

    • Stephen D. Turner
  10. Department of Pathology, University of Virginia, Charlottesville, Virginia 22903, USA

    • Kenneth S. Tung

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Contributions

C.Z.H. designed, performed and analysed most of the experiments in this study with input from K.S.R. I.J.J., J.M.K., M.W.B. assisted with in vivo experiments. A.L.K. provided phosphatidylserine liposomes. K.D. performed EM imaging of microvesicles. S.O-G ran the RNA-seq. U.E. performed microvesicle quantification using qNano. S.D.T. analysed the RNA-seq data. Y.M.S. performed airway resistance experiments. K.S.T. assisted in evaluation of lung pathology. C.Z.H. and K.S.R. wrote the manuscript with input from co-authors.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Kodi S. Ravichandran.

Reviewer Information Nature thanks L. Hedrick and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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    Supplementary Information

    This file contains the raw data for Figures 1b,g,n Extended Data Figures 1b, c-e, 2a and 4a,b.

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DOI

https://doi.org/10.1038/nature20141

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