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Macrophages redirect phagocytosis by non-professional phagocytes and influence inflammation

Nature volume 539, pages 570–574 (2016)Cite this article

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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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Figure 1: IGF-1 dampens apoptotic cell engulfment and enhances liposome uptake by non-professional phagocytes.
Figure 2: Macrophages produce IGF-1 during apoptotic cell clearance.
Figure 3: Mice lacking IGF-1R in airway epithelial cells have exacerbated airway inflammation.
Figure 4: IGF-1R expression in airway epithelial cells is required in the sensitization phase of airway inflammation.

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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

Authors and Affiliations

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

    Claudia Z. Han, Monica W. Buckley & Kodi S. Ravichandran

  3. Department of Medicine, University of Virginia, Charlottesville, 22903, Virginia, USA

    Alexander L. Klibanov, Yun M. Shim & Kenneth S. Tung

  4. Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, 22903, Virginia, USA

    Alexander L. Klibanov

  5. Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, 22903, Virginia, USA

    Kelly Dryden

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

    Suna Onengut-Gumuscu

  7. Center for Public Health Genomics, University of Virginia, Charlottesville, 22903, Virginia, USA

    Suna Onengut-Gumuscu

  8. Department of Medicine, Division of Nephrology, University of Virginia, Charlottesville, 22903, Virginia, USA

    Uta Erdbrügger

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

    Stephen D. Turner

  10. Department of Pathology, University of Virginia, Charlottesville, 22903, Virginia, USA

    Kenneth S. Tung

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  1. Claudia Z. Han
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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.

Corresponding author

Correspondence to Kodi S. Ravichandran.

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

Extended data figures and tables

Extended Data Figure 1 IGF-1, but not EGF, VEGF, PDFG-AA/-BB, suppresses phagocytosis of apoptotic cells in non-professional phagocytes.

a, Representative engulfment assay in which LR73 cells were treated with indicated growth factors at increasing concentrations and assessed for engulfment of apoptotic thymocytes (n = 3). b–e, Serum-starved LR73 cells were stimulated with 100 ng ml−1 of specified growth factors for indicated time and the phosphorylation of Erk1/2 was determined by immunoblotting (n = 2). f, g, Representative engulfment assay in which the uptake of apoptotic thymocytes by 16HBE14o- human airway epithelial cells (f) or SVEC-40 endothelial cells (g) is dampened by IGF-1 treatment (n = 3). Error bars represent s.d., P value of <0.001 (***).

Extended Data Figure 2 Insulin and IGF-II also decrease apoptotic cell engulfment, similar to IGF-1 that is reversed by treatment with NVP-AEW541.

a, Left, engulfment of apoptotic thymocytes by LR73 cells treated with various doses of NVP-AEW541, a small molecule inhibitor of IGF-1R (n = 3). Right, representative immunoblot of LR73 cells stimulated with IGF-1 and treated with increasing doses of NVP-AEW541 (n = 2). b, c, Engulfment of apoptotic thymocytes by LR73 cells treated with the indicated concentrations of human insulin (b) and human IGF-II (c) (n = 2). Error bars represent s.d.

Extended Data Figure 3 Blocking canonical signalling intermediates downstream of IGF-1 receptor signalling, Rho-kinase- or Arp2/3-mediated functions, does not reverse the IGF-1 mediated engulfment modulation.

a–f, Engulfment of apoptotic thymocytes by LR73 cells treated with U2016 (Erk1/2 inhibitor) (a), MK-2206 (Akt1/2/3 inhibitor) (b), Rapamycin (mTOR inhibitor) (c), or Wortmannin (PI 3-Kinase inhibitor) (d), Rho-kinase inhibitors Y27632 (e) or GSK269962 (f) in the presence or absence of IGF-1 (n = 2–3). Initially, it appeared that inhibition of Rho-kinase was able to partially rescue IGF-1 induced engulfment suppression. However, as Rho-kinase inhibition basally increases phagocytosis of apoptotic cells (consistent with what has been previously reported), we normalized the change in phagocytosis for each inhibitor concentration to the appropriate control (right panel). After normalizing, we observed that Rho-kinase inhibition did not increase apoptotic cell uptake in LR73 cells in the presence of IGF-1 more than the increase observed basally owing to Rho-kinase inhibition. Thus, inhibition of Rho-kinase does not appear to rescue IGF-1-induced engulfment suppression. g, LR73 cells were treated with CK-666 and then assessed for uptake of liposomes in the presence of IGF-1. Data represented as mean ± s.d.

Extended Data Figure 4 Macrophages express IGF-1R and phosphorylate IGF-1R upon IGF-1 stimulation, but engulf apoptotic cells at normal capacity when exposed to IGF-1 or insulin.

a, b, J774 cells (a) or LR73 cells (b) treated with 100 ng ml−1 mouse IGF-1 were assessed for their ability to engulf apoptotic thymocytes, or serum-starved for 6 h and stimulated with 100 ng ml−1 mouse IGF-1 and assessed for phosphorylation of IGF-1R by western blot. c, Flow cytometry histograms of IGF-1R expression on J774 cells (left), bone-marrow-derived macrophages (middle), and peritoneal macrophages (right) (n = 3–4). d, e, IC-21 cells treated with indicated concentrations of mouse IGF-1 (d) or human insulin (e) were assessed for their ability to engulf apoptotic thymocytes (n = 2–3). Error bars represent s.d.

Extended Data Figure 5 Production of IGF-1 by peritoneal macrophages after apoptotic cell or IL-4 stimulation correlates with new transcription.

a, Peritoneal macrophages were either untreated, stimulated with rIL-4 or apoptotic Jurkat cells and Igf1 mRNA (top panels) and IGF-1 protein in the supernatant (bottom panels) were assessed in a time course (n.d., not detected) (n = 3). Data represented as mean ± s.d. b, c, Lung sections from wild-type mice were stained with antibodies against alveolar macrophages (Mac-2), airway epithelial cells (CC-10), and IGF-1R. d, Alveolar macrophages isolated from LysM-Cre/Igf1fl/fl and littermate controls were assessed for Igf1 mRNA expression (n = 2 per group, data represented as mean ± s.e.m.).

Extended Data Figure 6 CCSP-Cre/Igf1rfl/fl mice exposed to HDM have greater airway resistance and show a trend towards greater immune cell infiltration in the lungs and more apoptotic cells.

a, Total cell counts of lung CD3+CD4+ T cells (left), CD3+CD4+CD44+ T cells (middle), and CD3+CD4+CD69+ T cells (right panel) in the lungs of CCSP-Cre/Igf1r+/+ and Igf1rfl/fl mice given the full HDM course. b, Airway hyper-responsiveness to methacholine (another measure of allergen sensitivity) in the CCSP-Cre/Igf1rfl/fl mice compared to control CCSP-Cre/Igf1r+/+ mice treated with HDM (n = 6–8 mice per group). c, Representative histology images of cleaved caspase (CC3) staining in lung sections of mice given the full HDM course. Black arrowheads indicate positive staining. Average CC3-positive cells per mouse are quantified on the right (n = 3 per group). Data represented as mean ± s.e.m. P value of <0.01 (**).

Extended Data Figure 7 Schematic IGF-1R deletion during the sensitization versus challenge phases of HDM administration, and the response of CCSP-Cre/Igf1r+/+ and Igf1rfl/fl mice in the second regime (the challenge phase).

a, Schematic describing the different time courses for Igf1r deletion from Club cells (induced via administration of doxycycline) and for the allergen HDM exposure. b, Total cell counts of various populations in the BAL fluid of CCSP-Cre/Igf1r+/+ and CCSP-Cre/Igf1rfl/fl mice given HDM according to the second regimen. c, Total cell counts of CD3+CD4+ T cells of draining lymph nodes of CCSP-Cre/Igf1r+/+ and CCSP-Cre/Igf1rfl/fl mice given HDM according to the second regimen. Data represented as mean ± s.e.m. NS, notsignificant. P value of <0.05 (*).

Extended Data Figure 8 Alveolar-macrophage-derived microvesicles suppress gene expression in lung epithelial cells exposed to HDM extract.

a, Microvesicles (MV) were collected from either control or IL-4-treated MH-S alveolar macrophages and then counted using qNano (n = 3). b, Supernatants from IL-4-treated MH-S macrophages were assessed for IGF-1 secretion. c, BEAS-2B cells were treated with HDM either in the presence or absence of alveolar-macrophage-derived microvesicles for 3 h and then assessed for expression of FGF2, KLF4, IFIT2, and PTX3 (n = 6). Data represented as mean ± s.e.m. P value of <0.01 (**), or <0.001 (***).

Extended Data Figure 9 Model for alveolar macrophage regulation of airway epithelial cells, with respect to particle uptake and the response to allergens, through IGF-1 and microvesicles.

Exposure of airways to allergens, such as HDM, can cause apoptotic cell death as well as IL-4 and IL-13 production, from mast cells and type-2 innate lymphoid cells (ILC2s). These cytokines, along with apoptotic cells, trigger alveolar macrophages to produce IGF-1. The released IGF-1 (a) then acts on the airway epithelium to elicit two actions: first, to decrease the uptake of apoptotic cells, and second, to enhance the uptake of macrophage-derived microvesicles. These microvesicles (b) dampen inflammatory cytokine production through airway epithelial cells.

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This file contains the raw data for Figures 1b,g,n Extended Data Figures 1b, c-e, 2a and 4a,b. (PDF 7269 kb)

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Han, C., Juncadella, I., Kinchen, J. et al. Macrophages redirect phagocytosis by non-professional phagocytes and influence inflammation. Nature 539, 570–574 (2016). https://doi.org/10.1038/nature20141

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