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A critical function for CD200 in lung immune homeostasis and the severity of influenza infection

Abstract

The lung must maintain a high threshold of immune 'ignorance' to innocuous antigens to avoid inflammatory disease that depends on the balance of positive inflammatory signals and repressor pathways. We demonstrate here that airway macrophages had higher expression of the negative regulator CD200 receptor (CD200R) than did their systemic counterparts. Lung macrophages were restrained by CD200 expressed on airway epithelium. Mice lacking CD200 had more macrophage activity and enhanced sensitivity to influenza infection, which led to delayed resolution of inflammation and, ultimately, death. The administration of agonists that bind CD200R, however, prevented inflammatory lung disease. Thus, CD200R is critical for lung macrophage immune homeostasis in the resting state and limits inflammatory amplitude and duration during pulmonary influenza infection.

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Figure 1: Expression of CD200 and CD200R expression in homeostasis.
Figure 2: Heightened responsiveness of Cd200−/− alveolar macrophages stimulated ex vivo.
Figure 3: Changes in CD200 and CD200R expression during influenza infection.
Figure 4: Enhanced inflammation in Cd200−/− mice infected with influenza.
Figure 5: Heightened myeloid and T cell responses in influenza-infected Cd200−/− mice.
Figure 6: CD200R signaling ameliorates influenza-induced inflammation.

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References

  1. Raz, E. Organ-specific regulation of innate immunity. Nat. Immunol. 8, 3–4 (2007).

    Article  CAS  Google Scholar 

  2. Matzinger, P. Friendly and dangerous signals: is the tissue in control? Nat. Immunol. 8, 11–13 (2007).

    Article  CAS  Google Scholar 

  3. Bingisser, R.M. & Holt, P.G. Immunomodulating mechanisms in the lower respiratory tract: nitric oxide mediated interactions between alveolar macrophages, epithelial cells, and T-cells. Swiss Med. Wkly. 131, 171–179 (2001).

    CAS  PubMed  Google Scholar 

  4. Munger, J.S. et al. The integrin αVβ6 binds and activates latent TGF-β1: a mechanism for regulating pulmonary inflammation and fibrosis. Cell 96, 319–328 (1999).

    Article  CAS  Google Scholar 

  5. Takabayshi, K. et al. Induction of a homeostatic circuit in lung tissue by microbial compounds. Immunity 24, 475–487 (2006).

    Article  CAS  Google Scholar 

  6. Morris, D.G. et al. Loss of integrin αVβ6-mediated TGF-β activation causes Mmp12-dependent emphysema. Nature 422, 169–173 (2003).

    Article  CAS  Google Scholar 

  7. Wright, G.J. et al. Lymphoid/neuronal cell surface OX2 glycoprotein recognizes a novel receptor on macrophages implicated in the control of their function. Immunity 13, 233–242 (2000).

    Article  CAS  Google Scholar 

  8. Wright, G.J. et al. Characterization of the CD200 receptor family in mice and humans and their interactions with CD200. J. Immunol. 171, 3034–3046 (2003).

    Article  CAS  Google Scholar 

  9. Zhang, S., Cherwinski, H., Sedgwick, J.D. & Phillips, J.H. Molecular mechanisms of CD200 inhibition of mast cell activation. J. Immunol. 173, 6786–6793 (2004).

    Article  CAS  Google Scholar 

  10. Cherwinski, H.M. et al. The CD200 receptor is a novel and potent regulator of murine and human mast cell function. J. Immunol. 174, 1348–1356 (2005).

    Article  CAS  Google Scholar 

  11. Shiratori, I. et al. Down-regulation of basophil function by human CD200 and human herpesvirus-8 CD200. J. Immunol. 175, 4441–4449 (2005).

    Article  CAS  Google Scholar 

  12. Barclay, A.N. & Ward, H.A. Purification and chemical characterisation of membrane glycoproteins from rat thymocytes and brain, recognised by monoclonal antibody MRC OX 2. Eur. J. Biochem. 129, 447–458 (1982).

    Article  CAS  Google Scholar 

  13. Hoek, R.M. et al. Down-regulation of the macrophage lineage through interaction with OX2 (CD200). Science 290, 1768–1771 (2000).

    Article  CAS  Google Scholar 

  14. Wright, G.J., Jones, M., Puklavec, M.J., Brown, M.H. & Barclay, A.N. The unusual distribution of the neuronal/lymphoid cell surface CD200 (OX2) glycoprotein is conserved in humans. Immunology 102, 173–179 (2001).

    Article  CAS  Google Scholar 

  15. Webb, M. & Barclay, A.N. Localisation of the MRC OX-2 glycoprotein on the surfaces of neurones. J. Neurochem. 43, 1061–1067 (1984).

    Article  CAS  Google Scholar 

  16. Dick, A.D., Broderick, C., Forrester, J.V. & Wright, G.J. Distribution of OX2 antigen and OX2 receptor within retina. Invest. Ophthalmol. Vis. Sci. 42, 170–176 (2001).

    CAS  PubMed  Google Scholar 

  17. Bukovsky, A., Presl, J. & Zidovsky, J. Association of some cell surface antigens of lymphoid cells and cell surface differentiation antigens with early rat pregnancy. Immunology 52, 631–640 (1984).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Nathan, C. & Muller, W.A. Putting the brakes on innate immunity: a regulatory role for CD200? Nat. Immunol. 2, 17–19 (2001).

    Article  CAS  Google Scholar 

  19. Chen, Z., Zeng, H. & Gorczynski, R.M. Cloning and characterization of the murine homologue of the rat/human MRC OX-2 gene. Biochim. Biophys. Acta 1362, 6–10 (1997).

    Article  Google Scholar 

  20. McCaughan, G.W., Clark, M.J. & Barclay, A.N. Characterization of the human homolog of the rat MRC OX-2 membrane glycoprotein. Immunogenetics 25, 329–335 (1987).

    Article  CAS  Google Scholar 

  21. de Heer, H.J., Hammad, H., Kool, M. & Lambrecht, B.N. Dendritic cell subsets and immune regulation in the lung. Semin. Immunol. 17, 295–303 (2005).

    Article  CAS  Google Scholar 

  22. Fernandez, S., Jose, P., Avdiushko, M.G., Kaplan, A.M. & Cohen, D.A. Inhibition of IL-10 receptor function in alveolar macrophages by Toll-like receptor agonists. J. Immunol. 172, 2613–2620 (2004).

    Article  CAS  Google Scholar 

  23. Tuthill, T.J. et al. Mouse respiratory epithelial cells support efficient replication of human rhinovirus. J. Gen. Virol. 84, 2829–2836 (2003).

    Article  CAS  Google Scholar 

  24. Gardai, S.J. et al. By binding SIRPα or calreticulin/CD91, lung collectins act as dual function surveillance molecules to suppress or enhance inflammation. Cell 115, 13–23 (2003).

    Article  CAS  Google Scholar 

  25. Mestecky, J., Russell, M.W. & Elson, C.O. Perspectives on mucosal vaccines: is mucosal tolerance a barrier? J. Immunol. 179, 5633–5638 (2007).

    Article  CAS  Google Scholar 

  26. Kong, X.N. et al. LPS-induced down-regulation of signal regulatory protein α contributes to innate immune activation in macrophages. J. Exp. Med. 204, 2719–2731 (2007).

    Article  CAS  Google Scholar 

  27. Liew, F.Y., Xu, D., Brint, E.K. & O'Neill, L.A. Negative regulation of Toll-like receptor–mediated immune responses. Nat. Rev. Immunol. 5, 446–458 (2005).

    Article  CAS  Google Scholar 

  28. Han, J. & Ulevitch, R.J. Limiting inflammatory responses during activation of innate immunity. Nat. Immunol. 6, 1198–1205 (2005).

    Article  CAS  Google Scholar 

  29. Carmody, R.J., Ruan, Q., Palmer, S., Hilliard, B. & Chen, Y.H. Negative regulation of Toll-like receptor signaling by NF-κB p50 ubiquitination blockade. Science 317, 675–678 (2007).

    Article  CAS  Google Scholar 

  30. Broderick, C. et al. Constitutive retinal CD200 expression regulates resident microglia and activation state of inflammatory cells during experimental autoimmune uveoretinitis. Am. J. Pathol. 161, 1669–1677 (2002).

    Article  CAS  Google Scholar 

  31. Taylor, N. et al. Enhanced tolerance to autoimmune uveitis in CD200–deficient mice correlates with a pronounced Th2 switch in response to antigen challenge. J. Immunol. 174, 143–154 (2005).

    Article  CAS  Google Scholar 

  32. Copland, D.A. et al. Monoclonal antibody–mediated CD200 receptor signaling suppresses macrophage activation and tissue damage in experimental autoimmune uveoretinitis. Am. J. Pathol. 171, 580–588 (2007).

    Article  CAS  Google Scholar 

  33. Banerjee, D. & Dick, A.D. Blocking CD200–CD200 receptor axis augments NOS-2 expression and aggravates experimental autoimmune uveoretinitis in Lewis rats. Ocul. Immunol. Inflamm. 12, 115–125 (2004).

    Article  CAS  Google Scholar 

  34. Karupiah, G., Chen, J.H., Mahalingam, S., Nathan, C.F. & MacMicking, J.D. Rapid interferon γ-dependent clearance of influenza A virus and protection from consolidating pneumonitis in nitric oxide synthase 2-deficient mice. J. Exp. Med. 188, 1541–1546 (1998).

    Article  CAS  Google Scholar 

  35. Akaike, T. Role of free radicals in viral pathogenesis and mutation. Rev. Med. Virol. 11, 87–101 (2001).

    Article  CAS  Google Scholar 

  36. Akaike, T. et al. Pathogenesis of influenza virus–induced pneumonia: involvement of both nitric oxide and oxygen radicals. Proc. Natl. Acad. Sci. USA 93, 2448–2453 (1996).

    Article  CAS  Google Scholar 

  37. Snelgrove, R.J., Edwards, L., Rae, A.J. & Hussell, T. An absence of reactive oxygen species improves the resolution of lung influenza infection. Eur. J. Immunol. 36, 1364–1373 (2006).

    Article  CAS  Google Scholar 

  38. Hussell, T., Pennycook, A. & Openshaw, P.J. Inhibition of tumor necrosis factor reduces the severity of virus-specific lung immunopathology. Eur. J. Immunol. 31, 2566–2573 (2001).

    Article  CAS  Google Scholar 

  39. Peper, R.L. & Van Campen, H. Tumor necrosis factor as a mediator of inflammation in influenza A viral pneumonia. Microb. Pathog. 19, 175–183 (1995).

    Article  CAS  Google Scholar 

  40. Cook, D.N. et al. Requirement of MIP-1 α for an inflammatory response to viral infection. Science 269, 1583–1585 (1995).

    Article  CAS  Google Scholar 

  41. Snelgrove, R.J., Edwards, L., Williams, A.E., Rae, A.J. & Hussell, T. In the absence of reactive oxygen species, T cells default to a Th1 phenotype and mediate protection against pulmonary Cryptococcus neoformans infection. J. Immunol. 177, 5509–5516 (2006).

    Article  CAS  Google Scholar 

  42. Lawrence, T., Gilroy, D.W., Colville-Nash, P.R. & Willoughby, D.A. Possible new role for NF-κB in the resolution of inflammation. Nat. Med. 7, 1291–1297 (2001).

    Article  CAS  Google Scholar 

  43. Barclay, A.N., Wright, G.J., Brooke, G. & Brown, M.H. CD200 and membrane protein interactions in the control of myeloid cells. Trends Immunol. 23, 285–290 (2002).

    Article  CAS  Google Scholar 

  44. Dong, K.K. et al. Adaptive immune cells temper initial innate responses. Nat. Med. 13, 1248–1252 (2007).

    Article  Google Scholar 

  45. Rosenblum, M.D. et al. CD200 is a novel p53-target gene involved in apoptosis–associated immune tolerance. Blood 103, 2691–2698 (2004).

    Article  CAS  Google Scholar 

  46. Gorczynski, R.M., Chen, Z., Yu, K. & Hu, J. CD200 immunoadhesin suppresses collagen-induced arthritis in mice. Clin. Immunol. 101, 328–334 (2001).

    Article  CAS  Google Scholar 

  47. Gorczynski, R.M., Chen, Z., Lee, L., Yu, K. & Hu, J. Anti–CD200R ameliorates collagen-induced arthritis in mice. Clin. Immunol. 104, 256–264 (2002).

    Article  CAS  Google Scholar 

  48. Gorczynski, R.M. et al. An immunoadhesin incorporating the molecule OX-2 is a potent immunosuppressant that prolongs allo- and xenograft survival. J. Immunol. 163, 1654–1660 (1999).

    CAS  PubMed  Google Scholar 

  49. Lipatov, A.S. et al. Pathogenesis of Hong Kong H5N1 influenza virus NS gene reassortants in mice: the role of cytokines and B- and T-cell responses. J. Gen. Virol. 86, 1121–1130 (2005).

    Article  CAS  Google Scholar 

  50. Chan, M.C. et al. Proinflammatory cytokine responses induced by influenza A (H5N1) viruses in primary human alveolar and bronchial epithelial cells. Respir. Res. 6, 135 (2005).

    Article  CAS  Google Scholar 

  51. de Jong, M.D. et al. Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia. Nat. Med. 12, 1203–1207 (2006).

    Article  CAS  Google Scholar 

  52. Peiris, J.S. et al. Re-emergence of fatal human influenza A subtype H5N1 disease. Lancet 363, 617–619 (2004).

    Article  CAS  Google Scholar 

  53. Boudakov, I. et al. Mice lacking CD200R1 show absence of suppression of lipopolysaccharide-induced tumor necrosis factor-α and mixed leukocyte culture responses by CD200. Transplantation 84, 251–257 (2007).

    Article  CAS  Google Scholar 

  54. Arase, H., Arase, N., Nakagawa, K., Good, R.A. & Onoe, K. NK1.1+ CD4+ CD8 thymocytes with specific lymphokine secretion. Eur. J. Immunol. 23, 307–310 (1993).

    Article  CAS  Google Scholar 

  55. Hussell, T., Spender, L.C., Georgiou, A., O'Garra, A. & Openshaw, P.J.M. Th1 and Th2 cytokine induction in pulmonary T-cells during infection with respiratory syncytial virus. J. Gen. Virol. 77, 2447–2455 (1996).

    Article  CAS  Google Scholar 

  56. Corti, M., Brody, A.R. & Harrison, J.H. Isolation and primary culture of murine alveolar type II cells. Am. J. Respir. Cell Mol. Biol. 14, 309–315 (1996).

    Article  CAS  Google Scholar 

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Acknowledgements

Influenza X31 virus was a gift from A. Douglas (National Institute for Medical Research, London); rat agonistic anti-mouse CD200R IgG1 was donated by N. Barclay (Oxford); and LA-4 cells were a gift from S. Johnston (Imperial College, London). Supported by the Medical Research Council (P171/03/C1/048), the US National Institutes of Health (NGA:1 U01 AI070232–01), the Wellcome Trust (082727/Z/07/Z) and the European Union (032296).

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Authors

Contributions

T.H. and R.J.S. planned, executed and interpreted the experiments and prepared the manuscript; J.G. did many experiments and finalized the figures for publication; A.M.D. assisted with the purification of airway epithelial cells and alveolar macrophages; D.L., S.V., L.E. and E.G. provided technical contributions to the paper; and J.D.S. and A.N.B. provided key reagents and contributed discussions throughout the work.

Corresponding author

Correspondence to Tracy Hussell.

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Competing interests

T.H. has stock in and is assisting StormBio to develop an H5N1 mouse model to be used for testing cytokine blockade; CD200 may be considered if appropriate. J.D.S. is employed by and has stock in Eli Lilly.

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Snelgrove, R., Goulding, J., Didierlaurent, A. et al. A critical function for CD200 in lung immune homeostasis and the severity of influenza infection. Nat Immunol 9, 1074–1083 (2008). https://doi.org/10.1038/ni.1637

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