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PTEN functions to 'prioritize' chemotactic cues and prevent 'distraction' in migrating neutrophils

Nature Immunology volume 9, pages 743–752 (2008)Cite this article

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Abstract

Neutrophils encounter and 'prioritize' many chemoattractants in their pursuit of bacteria. Here we tested the possibility that the phosphatase PTEN is responsible for the prioritization of chemoattractants. Neutrophils induced chemotaxis by two separate pathways, the phosphatidylinositol-3-OH kinase (PI(3)K) phosphatase and tensin homolog (PTEN) pathway, and the p38 mitogen-activated protein kinase pathway, with the p38 pathway dominating over the PI(3)K pathway. Pten−/− neutrophils could not prioritize chemoattractants and were 'distracted' by chemokines when moving toward bacterial chemoattractants. In opposing gradients, PTEN became distributed throughout the cell circumference, which inhibited all PI(3)K activity, thus permitting 'preferential' migration toward bacterial products via phospholipase A2 and p38. Such prioritization was defective in Pten−/− neutrophils, which resulted in defective bacterial clearance in vivo. Our data identify a PTEN-dependent mechanism in neutrophils to prioritize, 'triage' and integrate responses to multiple chemotactic cues.

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Figure 1: Function of PI(3)K and p38 in mediating the chemotaxis of mouse neutrophils to single and opposing gradients of chemoattractants.
Figure 2: Localization of PTEN and PtdIns(3,4,5)P3 in human neutrophils migrating to single gradients of fMLP or CXCL8.
Figure 3: Localization of PTEN and PtdIns(3,4,5)P3 in human neutrophils migrating in opposing gradients of fMLP and CXCL8.
Figure 4: Effect of PTEN deficiency on chemotaxis to a single gradient.
Figure 5: Function of PTEN in preventing distraction and regulating PI(3)K during chemotaxis to end-target chemoattractants.
Figure 6: Function of PTEN in mediating in vivo inflammatory responses.
Figure 7: Function of PTEN in regulating the extent of joint inflammation and neutrophil accumulation in an in vivo model of inflammatory arthritis.

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Change history

  • 21 July 2008

    In the version of this article initially published, phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2) is incorrectly identified as phosphatidylinositol-3,4-bisphosphate (PtdIns(3,4)P2). The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank C. Benoist (Harvard Medical School) for the KRN mouse line; T.W. Mak (University Health Network) for the loxP-flanked Pten mouse line; and M. Gaestel (Martin Luther University) for the MK2-deficient mice. Supported by the Canadian Institutes of Health Research (P.K.), the Arthritis Society of Canada (F.R.J.), the Alberta Heritage Foundation for Medical Research (P.K.), the Canada Research Chairs Program (P.K. and F.R.J.) and the Calvin, Phoebe and Joan Snyder Chair in Critical Care Research (P.K.).

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Authors and Affiliations

  1. Immunology Research Group, Institute of Infection and Immunity, University of Calgary, Calgary, T2N 4N1, Canada

    Bryan Heit, Zhiwen Guan, Pina Colarusso & Paul Kubes

  2. Department of Oncology, University of Calgary, Calgary, T2N 4N1, Canada

    Stephen M Robbins

  3. Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, T2N 4N1, Canada

    Stephen M Robbins

  4. The McCaig Institute for Bone and Joint Health, University of Calgary, Calgary, T2N 4N1, Canada

    Charlene M Downey, B Joan Miller & Frank R Jirik

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Contributions

B.H. did all experiments unless otherwise noted; C.D., B.J.M. and F.R.J. did the arthritis modeling and managed the bioimaging facility; S.R. provided molecular biology expertise and technical input; Z.G. did all p38 blotting; P.C. managed the imaging facility and aided in the development of the imaging assays; P.K. managed the study, and all experiments except the arthritis model were done in the laboratory of P.K.; and B.H. and P.K. prepared the manuscript with input from the other authors.

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Correspondence to Paul Kubes.

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Heit, B., Robbins, S., Downey, C. et al. PTEN functions to 'prioritize' chemotactic cues and prevent 'distraction' in migrating neutrophils. Nat Immunol 9, 743–752 (2008). https://doi.org/10.1038/ni.1623

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