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Capillary and arteriolar pericytes attract innate leukocytes exiting through venules and 'instruct' them with pattern-recognition and motility programs

Nature Immunology volume 14, pages 41–51 (2013)Cite this article

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Abstract

Coordinated navigation within tissues is essential for cells of the innate immune system to reach the sites of inflammatory processes, but the signals involved are incompletely understood. Here we demonstrate that NG2+ pericytes controlled the pattern and efficacy of the interstitial migration of leukocytes in vivo. In response to inflammatory mediators, pericytes upregulated expression of the adhesion molecule ICAM-1 and released the chemoattractant MIF. Arteriolar and capillary pericytes attracted and interacted with myeloid leukocytes after extravasating from postcapillary venules, 'instructing' them with pattern-recognition and motility programs. Inhibition of MIF neutralized the migratory cues provided to myeloid leukocytes by NG2+ pericytes. Hence, our results identify a previously unknown role for NG2+ pericytes as an active component of innate immune responses, which supports the immunosurveillance and effector function of extravasated neutrophils and macrophages.

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Figure 1: Pericytes sense inflammation and interact with cells of the innate immune system during interstitial migration.
Figure 2: The interaction of myeloid leukocytes with NG2+ pericytes during interstitial migration in vivo is mediated by ICAM-1.
Figure 3: Pericyte-derived MIF induces chemotaxis of cells of the innate immune system.
Figure 4: The accumulation of extravasated myeloid leukocytes around NG2+ cells depends on MIF.
Figure 5: NG2+ pericytes support the immunosurveillance function of extravasated neutrophils and provide tracks for fast interstitial leukocyte migration.
Figure 6: NG2+ pericytes guide LysM+ neutrophils to sites of sterile inflammation.
Figure 7: The effect of NG2+ pericytes on the pattern of interstitial migration of LysM+ neutrophils can be blocked by the MIF antagonist ISO-1.
Figure 8: The guidance signal provided by NG2+ pericytes to sites of sterile inflammation is blunted by the MIF antagonist ISO-1.

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Acknowledgements

We thank A. Suhr, N. Blount and A. Vens for technical assistance; T. Graf (Center for Genomic Regulation) for LysM-eGFP mice; and S. Jung (Weizmann Institute of Science) for CX3CR1-GFP mice. Supported by Collaborative Research Center SFB 914 (S.M., A.G.K., K.L. and B.W.), Deutsche Forschungsgemeinschaft Forschergruppe 923 (S.M.) and Framework Programme 7 of the European Union (PRESTIGE; S.M.).

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Authors and Affiliations

  1. Medizinische Klinik und Poliklinik I, Klinikum der Universität, Ludwig-Maximilians-Universität and Deutsches Herzzentrum München, Technische Universität München, Munich, Germany

    Konstantin Stark, Annekathrin Eckart, Selgai Haidari, Anca Tirniceriu, Michael Lorenz, Marie-Luise von Brühl, Florian Gärtner, Alexander Georg Khandoga, Kyle R Legate & Steffen Massberg

  2. Department of Applied Physics, Center for NanoSciences, Ludwig-Maximilians-Universität, Munich, Germany

    Kyle R Legate

  3. Department of Computer Science, Washington University, St. Louis, Missouri, USA

    Robert Pless

  4. Walter Brendel Centre of Experimental Medicine, Ludwig-Maximilians-Universität, Munich, Germany

    Ingrid Hepper & Barbara Walzog

  5. Department of Radiation Oncology, Division of Molecular Oncology, Ludwig-Maximilians-Universität, Munich, Germany

    Kirsten Lauber

  6. Munich Heart Alliance, a member of the German Center for Cardiovascular Research, Munich, Germany

    Steffen Massberg

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  1. Konstantin Stark
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Contributions

K.S., A.E., S.H. and S.M. conceived of and designed the experiments; K.S., A.E., S.H., A.G.K. and F.G. established and did two-photon microscopy; R.P. provided the code for the heat-map visualizations; K.S. and S.H. did cell tracking, three-dimensional rendering and heat-map visualizations; K.S., A.E. and M.-L.v.B. planned and did immunohistochemical and whole-mount staining; K.S., A.E., I.H. and B.W. designed and did chemotaxis assays; K.S., A.E., F.G. and K.L. designed and did adhesion and spreading assays; A.E., A.T. and M.L. did RT-PCR, flow cytometry and enzyme-linked immunosorbent assays; K.S., A.E. and S.M. analyzed the data; and K.S., A.E., K.L. and S.M. composed the manuscript.

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Correspondence to Steffen Massberg.

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Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–8 and Tables 1–2 (PDF 6507 kb)

Supplementary Video 1

NG2+ pericytes surrounding CD31+ endothelial cells. The video shows a whole mount staining of a microvascular vessel in the ear of an NG2DsRed mouse. NG2+ pericytes (red) in close contact to CD31+ endothelial cells (green), immunostained by a FITC labelled anti-CD31 antibody. Visualized by 2-photon microscopy. Still image is shown in Supplementary Figure 1d. (MOV 840 kb)

Supplementary Video 2

Interaction of a CX3CR1+ macrophage with a microvascular pericyte during interstitial migration in vivo. The video shows a vessel in the ear skin of an NG2DsRed- CX3CR1eGFP chimera with an NG2+ pericyte (red) around the capillary, stained by i.a. injection of FITC-Dextran (green). The colocalization (yellow, arrow) is zoomed with decreased density in the green and red channel. Inflammation was induced by s.c. injection of TNF and intravital 2-photon microscopy was performed 4 hrs later. A CX3CR1+ macrophage (green, arrowhead) is interacting with a pericyte over a time period of 20 min. Images were acquired at 2 images per minute and the sequence shows a 30 min time period. Still images are shown in Figure 1e. (MOV 1119 kb)

Supplementary Video 3

Interaction of a LysM+ neutrophil with a microvascular pericyte during interstitial migration in vivo. The video shows a polarized LysM+ neutrophil (green) sequentially interacting with NG2+ cells (red) in the ear skin of an NG2DsRed-LysMeGFP chimera. The track of the cell is shown in blue, colocalization is indicated by yellow. Inflammation was induced by s.c. injection of fMLP 2 hrs before the 2-photon imaging was performed. Images were acquired every 45 sec and the sequence shows a 15 min time period. Still image is shown in Figure 1f. (MOV 384 kb)

Supplementary Video 4

LysM+ cells contacting NG2+ cells during undirected interstitial migration. The video shows LysM+ neutrophils (green, cell 1-3) orientating towards NG2+ cells (red) during interstitial migration in the ear skin of an NG2DsRed-LysMeGFP chimera 2 hrs after injection of fMLP. After interaction cell 1 and cell 2 stay in close contact to NG2+ cells and sequentially interact (colocalization in yellow, arrowheads) with them (yellow/cyan track). Cell 3 interacts with a NG2+ cell (green track) and then establishes a long lasting contact (red track). Inflammation was induced by s.c. injection of fMLP 2 hrs before the 2-photon imaging was performed. Images were acquired every 30 sec and the sequence shows a time period of 1 hr. Still image is shown in Figure 2a. (MOV 823 kb)

Supplementary Video 5

CX3CR1+ cells contacting NG2+ cells during random interstitial migration. The video shows the ear skin of an NG2DsRed-CX3CR1eGFP chimera 4 hrs after s.c. injection of TNF. During undirected migration CX3CR1+ macrophages (green) interact with NG2+ cells (red) and stay in close contact to them. Interaction is visualized by colocalization (yellow). The tracks of cells are shown in different colors. Images were acquired at a rate of 2 images per minute and the sequence shows a time period of 50 min. Still image is shown in Figure 2c. (MOV 829 kb)

Supplementary Video 6

Heatmap visualization of LysM+ cell density over time after fMLP or fMLP and ISO-1 injection. Heatmap visualizations are superimposed on the video, color coding the density of interstitial LysM+ cells in the ear skin of NG2DsRed-LysMeGFP chimeras. Black/blue indicating low density, red/white marking areas of high density. Images were acquired at a rate of 2 images per minute by 2-PIVM and the sequence shows a time period of 55 min. Left: The video shows the ear skin 2 hrs after injection of fMLP. Initially, LysM+ cells (green) are diffusely distributed in the interstitial space. Over time, there is a concentration around NG2+ (red) cells. Still images are shown in Figure 4c. Right: The video shows the ear skin 2 hrs after injection of fMLP and 30 min after injection of ISO-1. LysM+ cells are diffusely distributed over the imaging area and there is no orientation towards NG2+ cells. Still images are shown in Figure 4f. (MOV 5772 kb)

Supplementary Video 7

Heatmap visualization of CX3CR1+ cell density over time after injection of TNFα and ISO-1. The video shows the ear skin of an NG2DsRed- CX3CR1eGFP chimera 4 hrs after injection of TNFα and 30 min after injection of ISO-1. A heatmap visualization is superimposed on the video, color coding the density of interstitial CX3CR1+ macrophages. Black/blue indicating low density, red/white marking areas of high density. The distribution of CX3CR1+ cells over the whole imaging area remains stable over the observation period and there is no concentration around NG2+ cells. Images were acquired at a rate of 2 images per minute and the sequence shows a time period of 45 min. Still images are shown in Supplementary Figure 4f. (MOV 702 kb)

Supplementary Video 8

LysM+ cells contacting NG2+ cells during directed interstitial migration induced by laser injury. The video shows the ear skin of an NG2DsRed-LysMeGFP chimera 45 min after induction of a focal necrosis (yellow) by laser treatment. On their way to the laser injury LysM+ neutrophils (green) are contacting NG2+ cells (red) and migrate along them. Interaction is visualized by colocalization (yellow). Images were acquired at a rate of 2 images per minute and the sequence shows a time period of 30 min. Still image is shown in Figure 6a. (MOV 5395 kb)

Supplementary Video 9

CX3CR1+ cells contacting NG2+ cells during interstitial migration induced by laser injury. The video shows the ear skin of an NG2DsRed-CX3CR1eGFP chimera 4 hrs after induction of localized necrosis by laser treatment. During directed migration CX3CR1+ macrophages (green) interact with NG2+ cells (red) and continue their path to the focus of sterile inflammation. Interaction is visualized by colocalization (yellow). The tracks of cells are shown in different colors. Images were acquired at a rate of 2 images per minute and the sequence shows a time period of 75 min. Still image is shown in Supplementary Figure 6g. (MOV 4160 kb)

Supplementary Video 10

LysM+ cells contacting NG2+ cells during interstitial migration induced by laser injury after treatment with ISO-1. The video shows the ear skin of an NG2DsRed-LysMeGFP chimera 45 min after induction of a focal necrosis (yellow) by laser treatment. ISO-1 was injected s.c. 30 min before the laser treatment. On their way to the laser injury LysM+ neutrophils (green) are contacting NG2+ cells (red), but do not follow them. The tracks of cells are shown in different colors. Images were acquired at a rate of 2 images per minute and the sequence shows a time period of 45 min. (MOV 2532 kb)

Supplementary Video 11

CX3CR1+ cells contacting NG2+ cells during interstitial migration induced by laser injury after treatment with ISO-1. The video shows the ear skin of an NG2DsRed-CX3CR1eGFP chimera 4 hrs after induction of localized necrosis by laser treatment. ISO-1 was injected 30 min before the laser injury. CX3CR1+ macrophages (green) shortly interact with NG2+ cells (red) on their way to the focus of sterile inflammation. The tracks of cells are shown in different colors. Images were acquired at a rate of 2 images per minute and the sequence shows a time period of 50 min. Still image is shown in Supplementary Figure 7g. (MOV 1408 kb)

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Stark, K., Eckart, A., Haidari, S. et al. Capillary and arteriolar pericytes attract innate leukocytes exiting through venules and 'instruct' them with pattern-recognition and motility programs. Nat Immunol 14, 41–51 (2013). https://doi.org/10.1038/ni.2477

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