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A signal-switch hypothesis for cross-regulation of cytokine and TLR signalling pathways

Nature Reviews Immunology volume 8, pages 816–822 (2008)Cite this article

Abstract

The importance of immunoreceptor tyrosine-based activation motif (ITAM)-coupled receptors in modulating signalling pathways downstream of other types of receptor is well established, but the mechanisms underlying this modulation are not known. Recent data suggest that calcium-dependent signalling downstream of ITAM-coupled receptors regulates the amplitude and functional outcomes of cytokine and TLR signalling. In this Opinion article, I describe a model whereby the intensity of ITAM-dependent signalling and the balance of calcium signals relative to other ITAM-mediated signalling pathways determines whether cellular responses to cytokines and TLR ligands are increased or inhibited. This model describes mechanisms that explain how ITAM-coupled receptors regulate heterologous signalling pathways.

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Figure 1: Canonical ITAM-mediated signalling in myeloid cells.
Figure 2: Tonic calcium signalling by low-avidity ligation of ITAM-coupled receptors modulates cytokine and TLR signalling.
Figure 3: High-intensity signalling after high-avidity ligation of ITAM-coupled receptors inhibits cytokine signalling but synergizes with TLR signalling.
Figure 4: Opposing effects of low- and high-avidity ligation of ITAM-coupled receptors are mediated by differential engagement of signalling pathways.

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References

  1. Romeo, C., Amiot, M. & Seed, B. Sequence requirements for induction of cytolysis by the T cell antigen/Fc receptor ζ chain. Cell 68, 889–897 (1992).

    Article  CAS  PubMed  Google Scholar 

  2. C. L. & Lowell, C. A. The expanding role for ITAM-based signaling pathways in immune cells. Sci. STKE 2007, re2 (2007).

  3. Ravetch, J. V. & Lanier, L. L. Immune inhibitory receptors. Science 290, 84–89 (2000).

    Article  CAS  PubMed  Google Scholar 

  4. Healy, J. I. et al. Different nuclear signals are activated by the B cell receptor during positive versus negative signaling. Immunity 6, 419–428 (1997).

    Article  CAS  PubMed  Google Scholar 

  5. Sloan-Lancaster, J., Shaw, A. S., Rothbard, J. B. & Allen, P. M. Partial T cell signaling: altered phospho-ζ and lack of zap70 recruitment in APL-induced T cell anergy. Cell 79, 913–922 (1994).

    Article  CAS  PubMed  Google Scholar 

  6. Barrow, A. D. & Trowsdale, J. You say ITAM and I say ITIM, let's call the whole thing off: the ambiguity of immunoreceptor signalling. Eur. J. Immunol. 36, 1646–1653 (2006).

    Article  CAS  PubMed  Google Scholar 

  7. Hamerman, J. A. & Lanier, L. L. Inhibition of immune responses by ITAM-bearing receptors. Sci. STKE 2006, re1 (2006).

  8. Turnbull, I. R. & Colonna, M. Activating and inhibitory functions of DAP12. Nature Rev. Immunol. 7, 155–161 (2007).

    Article  CAS  Google Scholar 

  9. Underhill, D. M. & Goodridge, H. S. The many faces of ITAMs. Trends Immunol. 28, 66–73 (2007).

    Article  CAS  PubMed  Google Scholar 

  10. Klesney-Tait, J., Turnbull, I. R. & Colonna, M. The TREM receptor family and signal integration. Nature Immunol. 7, 1266–1273 (2006).

    Article  CAS  Google Scholar 

  11. Tassiulas, I. et al. Amplification of IFN-α-induced STAT1 activation and inflammatory function by Syk and ITAM-containing adaptors. Nature Immunol. 5, 1181–1189 (2004).

    Article  CAS  Google Scholar 

  12. Wang, L. et al. 'Tuning' of type I interferon-induced Jak-STAT1 signaling by calcium-dependent kinases in macrophages. Nature Immunol. 9, 186–193 (2008).

    Article  CAS  Google Scholar 

  13. Kanamaru, Y. et al. Inhibitory ITAM signaling by FcαRI-FcRγ chain controls multiple activating responses and prevents renal inflammation. J. Immunol. 180, 2669–2678 (2008).

    Article  CAS  PubMed  Google Scholar 

  14. Pasquier, B. et al. Identification of FcαRI as an inhibitory receptor that controls inflammation: dual role of FcRγ ITAM. Immunity 22, 31–42 (2005).

    CAS  PubMed  Google Scholar 

  15. Pinheiro da Silva, F. et al. CD16 promotes Escherichia coli sepsis through an FcRγ inhibitory pathway that prevents phagocytosis and facilitates inflammation. Nature Med. 13, 1368–1374 (2007).

    Article  CAS  PubMed  Google Scholar 

  16. Kang, Y. J. et al. Calcineurin negatively regulates TLR-mediated activation pathways. J. Immunol. 179, 4598–4607 (2007).

    Article  CAS  PubMed  Google Scholar 

  17. Bezman, N. & Koretzky, G. A. Compartmentalization of ITAM and integrin signaling by adapter molecules. Immunol. Rev. 218, 9–28 (2007).

    Article  CAS  PubMed  Google Scholar 

  18. Borde, M., Barrington, R. A., Heissmeyer, V., Carroll, M. C. & Rao, A. Transcriptional basis of lymphocyte tolerance. Immunol. Rev. 210, 105–119 (2006).

    Article  CAS  PubMed  Google Scholar 

  19. Avraham, H., Park, S. Y., Schinkmann, K. & Avraham, S. RAFTK/Pyk2-mediated cellular signalling. Cell Signal 12, 123–133 (2000).

    Article  CAS  PubMed  Google Scholar 

  20. Hook, S. S. & Means, A. R. Ca2+/CaM-dependent kinases: from activation to function. Annu. Rev. Pharmacol. Toxicol. 41, 471–505 (2001).

    Article  CAS  PubMed  Google Scholar 

  21. Dolmetsch, R. E., Lewis, R. S., Goodnow, C. C. & Healy, J. I. Differential activation of transcription factors induced by Ca2+ response amplitude and duration. Nature 386, 855–858 (1997).

    Article  CAS  PubMed  Google Scholar 

  22. Gallo, E. M., Cante-Barrett, K. & Crabtree, G. R. Lymphocyte calcium signaling from membrane to nucleus. Nature Immunol. 7, 25–32 (2006).

    Article  CAS  Google Scholar 

  23. Mocsai, A. et al. The immunomodulatory adapter proteins DAP12 and Fc receptor γ-chain (FcRγ) regulate development of functional osteoclasts through the Syk tyrosine kinase. Proc. Natl Acad. Sci. USA 101, 6158–6163 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Hamerman, J. A. et al. Cutting Edge: inhibition of TLR and FcR responses in macrophages by triggering receptor expressed on myeloid cells (TREM)-2 and DAP12. J. Immunol. 177, 2051–2055 (2006).

    Article  CAS  PubMed  Google Scholar 

  25. Turnbull, I. R. et al. Cutting Edge: TREM-2 attenuates macrophage activation. J. Immunol. 177, 3520–3524 (2006).

    Article  CAS  PubMed  Google Scholar 

  26. Chu, C. L. et al. Increased TLR responses in dendritic cells lacking the ITAM-containing adapters DAP12 and FcRγ. Eur. J. Immunol. 38, 166–173 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Hamerman, J. A., Tchao, N. K., Lowell, C. A. & Lanier, L. L. Enhanced Toll-like receptor responses in the absence of signaling adaptor DAP12. Nature Immunol. 6, 579–586 (2005).

    Article  CAS  Google Scholar 

  28. Heissmeyer, V. et al. Calcineurin imposes T cell unresponsiveness through targeted proteolysis of signaling proteins. Nature Immunol. 5, 255–265 (2004).

    Article  CAS  Google Scholar 

  29. Abtahian, F. et al. Evidence for the requirement of ITAM domains but not SLP-76/Gads interaction for integrin signaling in hematopoietic cells. Mol. Cell Biol. 26, 6936–6949 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Mocsai, A. et al. Integrin signaling in neutrophils and macrophages uses adaptors containing immunoreceptor tyrosine-based activation motifs. Nature Immunol. 7, 1326–1333 (2006).

    Article  CAS  Google Scholar 

  31. Zou, W. et al. Syk, c-Src, the αvβ3 integrin, and ITAM immunoreceptors, in concert, regulate osteoclastic bone resorption. J. Cell Biol. 176, 877–888 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Dhodapkar, K. M. et al. Selective blockade of the inhibitory Fcγ receptor (FcγRIIB) in human dendritic cells and monocytes induces a type I interferon response program. J. Exp. Med. 204, 1359–1369 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Hu, X. et al. Sensitization of IFN-γ Jak–STAT signaling during macrophage activation. Nature Immunol. 3, 859–866 (2002).

    Article  CAS  Google Scholar 

  34. Pricop, L. et al. Differential modulation of stimulatory and inhibitory Fcγ receptors on human monocytes by TH1 and TH2 cytokines. J. Immunol. 166, 531–537 (2001).

    Article  CAS  PubMed  Google Scholar 

  35. Tridandapani, S. et al. Regulated expression and inhibitory function of FcγRIIb in human monocytic cells. J. Biol. Chem. 277, 5082–5089 (2002).

    Article  CAS  PubMed  Google Scholar 

  36. Takayanagi, H. Osteoimmunology: shared mechanisms and crosstalk between the immune and bone systems. Nature Rev. Immunol. 7, 292–304 (2007).

    Article  CAS  Google Scholar 

  37. Lee, S. H., Kim, T., Jeong, D., Kim, N. & Choi, Y. The Tec family tyrosine kinase Btk regulates RANKL-induced osteoclast maturation. J. Biol. Chem. 283, 11526–11534 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Shinohara, M. et al. Tyrosine kinases Btk and Tec regulate osteoclast differentiation by linking RANK and ITAM signals. Cell 132, 794–806 (2008).

    Article  CAS  PubMed  Google Scholar 

  39. Nimmerjahn, F. & Ravetch, J. V. Fcγ receptors as regulators of immune responses. Nature Rev. Immunol. 8, 34–47 (2008).

    Article  CAS  Google Scholar 

  40. Vivier, E., Nunes, J. A. & Vely, F. Natural killer cell signaling pathways. Science 306, 1517–1519 (2004).

    Article  CAS  PubMed  Google Scholar 

  41. Turnbull, I. R. et al. DAP12 (KARAP) amplifies inflammation and increases mortality from endotoxemia and septic peritonitis. J. Exp. Med. 202, 363–369 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Brown, G. D. et al. Dectin-1 mediates the biological effects of β-glucans. J. Exp. Med. 197, 1119–1124 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Gantner, B. N., Simmons, R. M., Canavera, S. J., Akira, S. & Underhill, D. M. Collaborative induction of inflammatory responses by dectin-1 and Toll-like receptor 2. J. Exp. Med. 197, 1107–1117 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Rogers, N. C. et al. Syk-dependent cytokine induction by Dectin-1 reveals a novel pattern recognition pathway for C type lectins. Immunity 22, 507–517 (2005).

    Article  CAS  PubMed  Google Scholar 

  45. Mosser, D. M. The many faces of macrophage activation. J. Leukoc. Biol. 73, 209–212 (2003).

    Article  CAS  PubMed  Google Scholar 

  46. Lee, I. H., Li, W. P., Hisert, K. B. & Ivashkiv, L. B. Inhibition of interleukin 2 signaling and signal transducer and activator of transcription (STAT)5 activation during T cell receptor-mediated feedback inhibition of T cell expansion. J. Exp. Med. 190, 1263–1274 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Zhu, J. et al. Transient inhibition of interleukin 4 signaling by T cell receptor ligation. J. Exp. Med. 192, 1125–1134 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Du, Z. et al. Selective regulation of IL-10 signaling and function by zymosan. J. Immunol. 176, 4785–4792 (2006).

    Article  CAS  PubMed  Google Scholar 

  49. Ji, J. D. et al. Inhibition of interleukin 10 signaling after Fc receptor ligation and during rheumatoid arthritis. J. Exp. Med. 197, 1573–1583 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Du, Z. et al. Inhibition of IFN-α signaling by a PKC- and protein tyrosine phosphatase SHP-2-dependent pathway. Proc. Natl Acad. Sci. USA 102, 10267–10272 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Yoshimura, A., Naka, T. & Kubo, M. SOCS proteins, cytokine signalling and immune regulation. Nature Rev. Immunol. 7, 454–465 (2007).

    Article  CAS  Google Scholar 

  52. Ahmed, S. T. & Ivashkiv, L. B. Inhibition of IL-6 and IL-10 signaling and Stat activation by inflammatory and stress pathways. J. Immunol. 165, 5227–5237 (2000).

    Article  CAS  PubMed  Google Scholar 

  53. Ahmed, S. T., Mayer, A., Ji, J. D. & Ivashkiv, L. B. Inhibition of IL-6 signaling by a p38-dependent pathway occurs in the absence of new protein synthesis. J. Leukoc. Biol. 72, 154–162 (2002).

    CAS  PubMed  Google Scholar 

  54. Bode, J. G. et al. TNF-α induces tyrosine phosphorylation and recruitment of the Src homology protein-tyrosine phosphatase 2 to the gp130 signal-transducing subunit of the IL-6 receptor complex. J. Immunol. 171, 257–266 (2003).

    Article  CAS  PubMed  Google Scholar 

  55. Fischer, P. et al. The role of the inhibitors of interleukin-6 signal transduction SHP2 and SOCS3 for desensitization of interleukin-6 signalling. Biochem. J. 378, 449–460 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Radtke, S. et al. Pro-inflammatory cytokines restrict IL-6 signaling through p38/MK2-mediated internalization and degradation of gp130. Cytokines in Health and Disease Abstract 223 [http://www.cytokines2007.org/abstracts2.pdf]. 15th Annual Meeting of the International Cytokine Society. (2007).

    Google Scholar 

  57. Sengupta, T. K., Schmitt, E. M. & Ivashkiv, L. B. Inhibition of cytokines and JAK-STAT activation by distinct signaling pathways. Proc. Natl Acad. Sci. USA 93, 9499–9504 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Kalliolias, G. & Ivashkiv, L. B. IL-27 activates human monocytes via STAT1 and suppresses IL-10 production but the inflammatory functions of IL-27 are abrogated by TLRs and p38. J. Immunol. 180, 6325–6333 (2008).

    Article  CAS  PubMed  Google Scholar 

  59. Park, J. H. et al. 'Coreceptor tuning': cytokine signals transcriptionally tailor CD8 coreceptor expression to the self-specificity of the TCR. Nature Immunol. 8, 1049–1059 (2007).

    Article  CAS  Google Scholar 

  60. Park-Min., K. H. et al. FcγRIII-dependent inhibition of interferon-γ responses mediates suppressive effects of intravenous immune globulin. Immunity 26, 67–78 (2007).

    Article  CAS  PubMed  Google Scholar 

  61. Ochi, S. et al. Pathological role of osteoclast costimulation in arthritis-induced bone loss. Proc. Natl Acad. Sci. USA 104, 11394–11399 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

I thank M. Nakamura for discussions and S. Goldring and X. Hu for critical review of the manuscript. This work was supported by grants from the National Institutes of Health.

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  1. Lionel B. Ivashkiv is at the Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, 535 East 70th Street, New York, New York 10021, USA. IvashkivL@hss.edu,

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Ivashkiv, L. A signal-switch hypothesis for cross-regulation of cytokine and TLR signalling pathways. Nat Rev Immunol 8, 816–822 (2008). https://doi.org/10.1038/nri2396

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