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CX3CR1 is required for airway inflammation by promoting T helper cell survival and maintenance in inflamed lung

Nature Medicine volume 16, pages 1305–1312 (2010)Cite this article

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Abstract

Allergic asthma is a T helper type 2 (TH2)-dominated disease of the lung. In people with asthma, a fraction of CD4+ T cells express the CX3CL1 receptor, CX3CR1, and CX3CL1 expression is increased in airway smooth muscle, lung endothelium and epithelium upon allergen challenge. Here we found that untreated CX3CR1-deficient mice or wild-type (WT) mice treated with CX3CR1-blocking reagents show reduced lung disease upon allergen sensitization and challenge. Transfer of WT CD4+ T cells into CX3CR1-deficient mice restored the cardinal features of asthma, and CX3CR1-blocking reagents prevented airway inflammation in CX3CR1-deficient recipients injected with WT TH2 cells. We found that CX3CR1 signaling promoted TH2 survival in the inflamed lungs, and injection of B cell leukemia/lymphoma-2 protein (BCl-2)-transduced CX3CR1-deficient TH2 cells into CX3CR1-deficient mice restored asthma. CX3CR1-induced survival was also observed for TH1 cells upon airway inflammation but not under homeostatic conditions or upon peripheral inflammation. Therefore, CX3CR1 and CX3CL1 may represent attractive therapeutic targets in asthma.

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Figure 1: Airway disease in CX3CR1-deficient mice.
Figure 2: AHR, airway inflammation and cytokine response in mice treated with CX3CR1 blocking reagents.
Figure 3: Airway disease in T cell–injected mice.
Figure 4: Number and phenotype of CX3CR1-expressing CD4+ T cells.
Figure 5: Frequency and phenotype of injected TH2 cells.
Figure 6: T cell proliferation and apoptosis.

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References

  1. Wills-Karp, M. Immunologic basis of antigen-induced airway hyperresponsiveness. Annu. Rev. Immunol. 17, 255–281 (1999).

    Article  CAS  Google Scholar 

  2. Robinson, D.S. et al. Predominant TH2-like bronchoalveolar T-lymphocyte population in atopic asthma. N. Engl. J. Med. 326, 298–304 (1992).

    Article  CAS  Google Scholar 

  3. Bazan, J.F. et al. A new class of membrane-bound chemokine with a CX3C motif. Nature 385, 640–644 (1997).

    Article  CAS  Google Scholar 

  4. Papadopoulos, E.J. et al. Fractalkine, a CX3C chemokine, is expressed by dendritic cells and is up-regulated upon dendritic cell maturation. Eur. J. Immunol. 29, 2551–2559 (1999).

    Article  CAS  Google Scholar 

  5. Muehlhoefer, A. et al. Fractalkine is an epithelial and endothelial cell-derived chemoattractant for intraepithelial lymphocytes in the small intestinal mucosa. J. Immunol. 164, 3368–3376 (2000).

    Article  CAS  Google Scholar 

  6. Nanki, T. et al. Inhibition of fractalkine ameliorates murine collagen-induced arthritis. J. Immunol. 173, 7010–7016 (2004).

    Article  CAS  Google Scholar 

  7. Yajima, N. et al. Elevated levels of soluble fractalkine in active systemic lupus erythematosus: potential involvement in neuropsychiatric manifestations. Arthritis Rheum. 52, 1670–1675 (2005).

    Article  CAS  Google Scholar 

  8. Imai, T. et al. Identification and molecular characterization of fractalkine receptor CX3CR1, which mediates both leukocyte migration and adhesion. Cell 91, 521–530 (1997).

    Article  CAS  Google Scholar 

  9. Geissmann, F., Jung, S. & Littman, D.R. Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity 19, 71–82 (2003).

    Article  CAS  Google Scholar 

  10. Jung, S. et al. Analysis of fractalkine receptor CX(3)CR1 function by targeted deletion and green fluorescent protein reporter gene insertion. Mol. Cell. Biol. 20, 4106–4114 (2000).

    Article  CAS  Google Scholar 

  11. Foussat, A. et al. Fractalkine receptor expression by T lymphocyte subpopulations and in vivo production of fractalkine in human. Eur. J. Immunol. 30, 87–97 (2000).

    Article  CAS  Google Scholar 

  12. Fraticelli, P. et al. Fractalkine (CX3CL1) as an amplification circuit of polarized TH1 responses. J. Clin. Invest. 107, 1173–1181 (2001).

    Article  CAS  Google Scholar 

  13. Nishimura, M. et al. Dual functions of fractalkine/CX3C ligand 1 in trafficking of perforin+/granzyme B+ cytotoxic effector lymphocytes that are defined by CX3CR1 expression. J. Immunol. 168, 6173–6180 (2002).

    Article  CAS  Google Scholar 

  14. Lesnik, P., Haskell, C.A. & Charo, I.F. Decreased atherosclerosis in Cx3cr1−/− mice reveals a role for fractalkine in atherogenesis. J. Clin. Invest. 111, 333–340 (2003).

    Article  CAS  Google Scholar 

  15. Inoue, A. et al. Antagonist of fractalkine (CX3CL1) delays the initiation and ameliorates the progression of lupus nephritis in MRL/lpr mice. Arthritis Rheum. 52, 1522–1533 (2005).

    Article  CAS  Google Scholar 

  16. Suzuki, F. et al. Inhibition of CX3CL1 (fractalkine) improves experimental autoimmune myositis in SJL/J mice. J. Immunol. 175, 6987–6996 (2005).

    Article  CAS  Google Scholar 

  17. Echigo, T., Hasegawa, M., Shimada, Y., Takehara, K. & Sato, S. Expression of fractalkine and its receptor, CX3CR1, in atopic dermatitis: possible contribution to skin inflammation. J. Allergy Clin. Immunol. 113, 940–948 (2004).

    Article  CAS  Google Scholar 

  18. Rimaniol, A.C. et al. The CX3C chemokine fractalkine in allergic asthma and rhinitis. J. Allergy Clin. Immunol. 112, 1139–1146 (2003).

    Article  CAS  Google Scholar 

  19. El-Shazly, A. et al. Fraktalkine produced by airway smooth muscle cells contributes to mast cell recruitment in asthma. J. Immunol. 176, 1860–1868 (2006).

    Article  CAS  Google Scholar 

  20. Tremblay, K. et al. Association study between the CX3CR1 gene and asthma. Genes Immun. 7, 632–639 (2006).

    Article  CAS  Google Scholar 

  21. Depner, M. et al. CX3CR1 Polymorphisms are associated with atopy but not asthma in German children. Int. Arch. Allergy Immunol. 144, 91–94 (2007).

    Article  CAS  Google Scholar 

  22. Cohn, L., Homer, R.J., Marinov, A., Rankin, J. & Bottomly, K. Induction of airway mucus production By T helper 2 (TH2) cells: a critical role for interleukin 4 in cell recruitment but not mucus production. J. Exp. Med. 186, 1737–1747 (1997).

    Article  CAS  Google Scholar 

  23. Chvatchko, Y. et al. A key role for CC chemokine receptor 4 in lipopolysaccharide-induced endotoxic shock. J. Exp. Med. 191, 1755–1764 (2000).

    Article  CAS  Google Scholar 

  24. Humbles, A.A. et al. The murine CCR3 receptor regulates both the role of eosinophils and mast cells in allergen-induced airway inflammation and hyperresponsiveness. Proc. Natl. Acad. Sci. USA 99, 1479–1484 (2002).

    Article  CAS  Google Scholar 

  25. Conroy, D.M. et al. CCR4 blockade does not inhibit allergic airways inflammation. J. Leukoc. Biol. 74, 558–563 (2003).

    Article  CAS  Google Scholar 

  26. Kawasaki, S. et al. Intervention of thymus and activation-regulated chemokine attenuates the development of allergic airway inflammation and hyperresponsiveness in mice. J. Immunol. 166, 2055–2062 (2001).

    Article  CAS  Google Scholar 

  27. Mikhak, Z. et al. Contribution of CCR4 and CCR8 to antigen-specific TH2 cell trafficking in allergic pulmonary inflammation. J. Allergy Clin. Immunol. 123, 67–73.e3 (2009).

    Article  CAS  Google Scholar 

  28. Chung, C.D. et al. CCR8 is not essential for the development of inflammation in a mouse model of allergic airway disease. J. Immunol. 170, 581–587 (2003).

    Article  CAS  Google Scholar 

  29. Chensue, S.W. et al. Aberrant in vivo T helper type 2 cell response and impaired eosinophil recruitment in CC chemokine receptor 8 knockout mice. J. Exp. Med. 193, 573–584 (2001).

    Article  CAS  Google Scholar 

  30. Goya, I. et al. Absence of CCR8 does not impair the response to ovalbumin-induced allergic airway disease. J. Immunol. 170, 2138–2146 (2003).

    Article  CAS  Google Scholar 

  31. Gonzalo, J.A. et al. Critical involvement of the chemotactic axis CXCR4/stromal cell-derived factor-1α in the inflammatory component of allergic airway disease. J. Immunol. 165, 499–508 (2000).

    Article  CAS  Google Scholar 

  32. Lukacs, N.W., Berlin, A., Schols, D., Skerlj, R.T. & Bridger, G.J. AMD3100, a CxCR4 antagonist, attenuates allergic lung inflammation and airway hyperreactivity. Am. J. Pathol. 160, 1353–1360 (2002).

    Article  CAS  Google Scholar 

  33. Liu, X. et al. The CC chemokine ligand 2 (CCL2) mediates fibroblast survival through IL-6. Am. J. Respir. Cell Mol. Biol. 37, 121–128 (2007).

    Article  CAS  Google Scholar 

  34. Hippe, A., Homey, B. & Mueller-Homey, A. Chemokines. Recent Results Cancer Res. 180, 35–50 (2010).

    Article  CAS  Google Scholar 

  35. Nie, Y., Han, Y.C. & Zou, Y.R. CXCR4 is required for the quiescence of primitive hematopoietic cells. J. Exp. Med. 205, 777–783 (2008).

    Article  CAS  Google Scholar 

  36. Linge, H.M. et al. The human CXC chemokine granulocyte chemotactic protein 2 (GCP-2)/CXCL6 possesses membrane-disrupting properties and is antibacterial. Antimicrob. Agents Chemother. 52, 2599–2607 (2008).

    Article  CAS  Google Scholar 

  37. Linge, H.M. et al. The antibacterial chemokine MIG/CXCL9 is constitutively expressed in epithelial cells of the male urogenital tract and is present in seminal plasma. J. Interferon Cytokine Res. 28, 191–196 (2008).

    Article  CAS  Google Scholar 

  38. Yang, D. et al. Many chemokines including CCL20/MIP-3alpha display antimicrobial activity. J. Leukoc. Biol. 74, 448–455 (2003).

    Article  CAS  Google Scholar 

  39. Benamar, K., Geller, E.B. & Adler, M.W. Elevated level of the proinflammatory chemokine, RANTES/CCL5, in the periaqueductal grey causes hyperalgesia in rats. Eur. J. Pharmacol. 592, 93–95 (2008).

    Article  CAS  Google Scholar 

  40. Milligan, E.D., Sloane, E.M. & Watkins, L.R. Glia in pathological pain: a role for fractalkine. J. Neuroimmunol. 198, 113–120 (2008).

    Article  CAS  Google Scholar 

  41. Miller, R.J., Jung, H., Bhangoo, S.K. & White, F.A. Cytokine and chemokine regulation of sensory neuron function. Handb. Exp. Pharmacol. 194, 417–449 (2009).

    Article  CAS  Google Scholar 

  42. Meucci, O. et al. Chemokines regulate hippocampal neuronal signaling and gp120 neurotoxicity. Proc. Natl. Acad. Sci. USA 95, 14500–14505 (1998).

    Article  CAS  Google Scholar 

  43. Landsman, L. et al. CX3CR1 is required for monocyte homeostasis and atherogenesis by promoting cell survival. Blood 113, 963–972 (2008).

    Article  Google Scholar 

  44. Garin, A., Pellet, P., Deterre, P., Debre, P. & Combadiere, C. Cloning and functional characterization of the human fractalkine receptor promoter regions. Biochem. J. 368, 753–760 (2002).

    Article  CAS  Google Scholar 

  45. Chen, S., Luo, D., Streit, W.J. & Harrison, J.K. TGF-β1 upregulates CX3CR1 expression and inhibits fractalkine-stimulated signaling in rat microglia. J. Neuroimmunol. 133, 46–55 (2002).

    Article  CAS  Google Scholar 

  46. Ramos, M.V. et al. Interleukin-10 and interferon-γ modulate surface expression of fractalkine-receptor (CX(3)CR1) via PI3K in monocytes. Immunology 129, 600–609 (2010).

    Article  CAS  Google Scholar 

  47. El Biaze, M. et al. T cell activation, from atopy to asthma: more a paradox than a paradigm. Allergy 58, 844–853 (2003).

    Article  CAS  Google Scholar 

  48. Boniface, S. et al. Assessment of T lymphocyte cytokine production in induced sputum from asthmatics: a flow cytometry study. Clin. Exp. Allergy 33, 1238–1243 (2003).

    Article  CAS  Google Scholar 

  49. Cho, S.H., Stanciu, L.A., Holgate, S.T. & Johnston, S.L. Increased interleukin-4, interleukin-5, and interferon-γ in airway CD4+ and CD8+ T cells in atopic asthma. Am. J. Respir. Crit. Care Med. 171, 224–230 (2005).

    Article  Google Scholar 

  50. Mamessier, E. et al. T-cell activation during exacerbations: a longitudinal study in refractory asthma. Allergy 63, 1202–1210 (2008).

    Article  CAS  Google Scholar 

  51. Lopez Vina, A. Severe asthma refractory to treatment: concepts and realities. Arch. Bronconeumol. 42, 20–25 (2006).

    Article  Google Scholar 

  52. O'Byrne, P.M. The demise of anti IL-5 for asthma, or not. Am. J. Respir. Crit. Care. Med. 176, 1059–1060 (2007).

    Article  Google Scholar 

  53. Wang, Q. et al. CD4 promotes breadth in the TCR repertoire. J. Immunol. 167, 4311–4320 (2001).

    Article  CAS  Google Scholar 

  54. Kheradmand, F. et al. A protease-activated pathway underlying TH cell type 2 activation and allergic lung disease. J. Immunol. 169, 5904–5911 (2002).

    Article  CAS  Google Scholar 

  55. Mougneau, E. et al. Expression cloning of a Leishmania major protective T cell antigen. Science 268, 563–566 (1995).

    Article  CAS  Google Scholar 

  56. Hamelmann, E. et al. Primary prevention of allergy: avoiding risk or providing protection? Clin. Exp. Allergy 38, 233–245 (2008).

    Article  CAS  Google Scholar 

  57. Verhasselt, V. et al. Breast milk-mediated transfer of an antigen induces tolerance and protection from allergic asthma. Nat. Med. 14, 170–175 (2008).

    Article  CAS  Google Scholar 

  58. Honda, K., Marquillies, P., Capron, M. & Dombrowicz, D. Peroxisome proliferator-activated receptor gamma is expressed in airways and inhibits features of airway remodeling in a mouse asthma model. J. Allergy Clin. Immunol. 113, 882–888 (2004).

    Article  CAS  Google Scholar 

  59. Humbles, A.A. et al. A critical role for eosinophils in allergic airways remodeling. Science 305, 1776–1779 (2004).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank N. Guy, V. Thieffin and A. Barbot for animal care, J. Cazareth and F. Larbret for cell sorting and S. Kirschnek (Institute for Medical Microbiology, Immunology and Hygiene, Technical University Munich) for providing the MIG-mBcl-2 and MIGR1 vectors. IFN-γ–specific antibody R4-6A2 and IL-4–specific antibody 11B11 were kind gifts from DNAX Research Institute. Cx3cr1GFP/GFP mice were a gift from S. Jung (Weizmann Institute of Science, Immunology Department). This research was supported by the Fondation pour la Recherche Medical, the Agence Nationale de la Recherche, the French Society of Allergology, the French Pneumologie Society, the Genavie foundation and the Pays de la Loire and Provence Alpes Cote d'Azur regional councils.

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Authors and Affiliations

  1. University of Nice-Sophia Antipolis, U924, Valbonne, France.,

    Cyrille Mionnet, Vanessa Buatois, Valerie Milcent, Nicolas Glaichenhaus & Valerie Julia

  2. Institut National de la Santé et de la Recherche Médicale, Paris, France

    Cyrille Mionnet, Vanessa Buatois, Akira Kanda, Valerie Milcent, Sebastien Fleury, David Lair, Marie Langelot, Yannick Lacoeuille, Antoine Magnan, David Dombrowicz, Nicolas Glaichenhaus & Valerie Julia

  3. University of Lille 2, U1011, Lille, France.,

    Akira Kanda, Sebastien Fleury & David Dombrowicz

  4. Institut Pasteur de Lille, Lille, France

    Akira Kanda, Sebastien Fleury & David Dombrowicz

  5. University of Nantes, UMR915, Institut du Thorax, Nantes, France

    David Lair, Marie Langelot, Yannick Lacoeuille & Antoine Magnan

  6. Dynavax Technologies, Berkeley, California, USA

    Edith Hessel & Robert Coffman

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Contributions

C.M. and V.B. conducted most of the experiments and contributed to data analysis. A.K., S.F. and D.D. measured lung resistance and compliance and performed lung histology. V.M. provided technical help. D.L., M.L., Y.L. and A.M. performed experiments with HDM. E.H. and R.C. contributed to early experiments aimed at monitoring chemokine receptor expression in lung T cells. N.G. and V.J. wrote the manuscript. V.J. conceived of and directed the project.

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Correspondence to Valerie Julia.

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Mionnet, C., Buatois, V., Kanda, A. et al. CX3CR1 is required for airway inflammation by promoting T helper cell survival and maintenance in inflamed lung. Nat Med 16, 1305–1312 (2010). https://doi.org/10.1038/nm.2253

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