Integrin CD11b positively regulates TLR4-induced signalling pathways in dendritic cells but not in macrophages

Abstract

Tuned and distinct responses of macrophages and dendritic cells to Toll-like receptor 4 (TLR4) activation induced by lipopolysaccharide (LPS) underpin the balance between innate and adaptive immunity. However, the molecule(s) that confer these cell-type-specific LPS-induced effects remain poorly understood. Here we report that the integrin α M (CD11b) positively regulates LPS-induced signalling pathways selectively in myeloid dendritic cells but not in macrophages. In dendritic cells, which express lower levels of CD14 and TLR4 than macrophages, CD11b promotes MyD88-dependent and MyD88-independent signalling pathways. In particular, in dendritic cells CD11b facilitates LPS-induced TLR4 endocytosis and is required for the subsequent signalling in the endosomes. Consistent with this, CD11b deficiency dampens dendritic cell-mediated TLR4-triggered responses in vivo leading to impaired T-cell activation. Thus, by modulating the trafficking and signalling functions of TLR4 in a cell-type-specific manner CD11b fine tunes the balance between adaptive and innate immune responses initiated by LPS.

References 42

1. 1.

   Zanoni I. & Granucci F. Differences in lipopolysaccharide-induced signaling between conventional dendritic cells and macrophages. Immunobiology 215, 709–712 (2010 ).

   Not in our library10.1016/j.imbio.2010.05.026

2. 2.

   Hashimoto D., Miller J. & Merad M. Dendritic cell and macrophage heterogeneity in vivo. Immunity 35, 323–335 (2011 ).

   Not in our library10.1016/j.immuni.2011.09.007

3. 3.

   Zanoni I. et al. CD14 controls the LPS-induced endocytosis of Toll-like receptor 4. Cell 147, 868–880 (2011 ).

   Not in our library10.1016/j.cell.2011.09.051

4. 4.

   Kagan J. C. & Medzhitov R. Phosphoinositide-mediated adaptor recruitment controls Toll-like receptor signaling. Cell 125, 943–955 (2006 ).

   Not in our library10.1016/j.cell.2006.03.047

5. 5.

   Ostuni R., Zanoni I. & Granucci F. Deciphering the complexity of Toll-like receptor signaling. Cell Mol. Life Sci. 67, 4109–4134 (2010 ).

   Not in our library10.1007/s00018-010-0464-x

6. 6.

   Fitzgerald K. A. et al. LPS-TLR4 signaling to IRF-3/7 and NF-kappaB involves the toll adapters TRAM and TRIF. J. Exp. Med. 198, 1043–1055 (2003 ).

   Not in our library10.1084/jem.20031023

7. 7.

   Kagan J. C. et al. TRAM couples endocytosis of Toll-like receptor 4 to the induction of interferon-beta. Nat. Immunol. 9, 361–368 (2008 ).

   Not in our library10.1038/ni1569

8. 8.

   Triantafilou M. & Triantafilou K. Lipopolysaccharide recognition: CD14, TLRs and the LPS-activation cluster. Trends. Immunol. 23, 301–304 (2002 ).

   Not in our library10.1016/s1471-4906(02)02233-0

9. 9.

   Ross G. D. Role of the lectin domain of Mac-1/CR3 (CD11b/CD18) in regulating intercellular adhesion. Immunol. Res. 25, 219–227 (2002 ).

   Not in our library10.1385/ir:25:3:219

10. 10.

    Abram C. L. & Lowell C. A. The ins and outs of leukocyte integrin signaling. Annu. Rev. Immunol. 27, 339–362 (2009 ).

    Not in our library10.1146/annurev.immunol.021908.132554

11. 11.

    Hajishengallis G. & Lambris J. D. Crosstalk pathways between Toll-like receptors and the complement system. Trends. Immunol. 31, 154–163 (2010 ).

    Not in our library10.1016/j.it.2010.01.002

12. 12.

    Wang L. et al. Indirect inhibition of Toll-like receptor and type I interferon responses by ITAM-coupled receptors and integrins. Immunity 32, 518–530 (2010 ).

    Not in our library10.1016/j.immuni.2010.03.014

13. 13.

    Fan S. T. & Edgington T. S. Coupling of the adhesive receptor CD11b/CD18 to functional enhancement of effector macrophage tissue factor response. J. Clin. Invest. 87, 50–57 (1991 ).

    Not in our library10.1172/jci115000

14. 14.

    Rezzonico R., Imbert V., Chicheportiche R. & Dayer J. M. Ligation of CD11b and CD11c beta(2) integrins by antibodies or soluble CD23 induces macrophage inflammatory protein 1alpha (MIP-1alpha) and MIP-1beta production in primary human monocytes through a pathway dependent on nuclear factor-kappaB. Blood 97, 2932–2940 (2001 ).

    Not in our library10.1182/blood.v97.10.2932

15. 15.

    Han C. et al. Integrin CD11b negatively regulates TLR-triggered inflammatory responses by activating Syk and promoting degradation of MyD88 and TRIF via Cbl-b. Nat. Immunol. 11, 734–742 (2010 ).

    Not in our library10.1038/ni.1908

16. 16.

    Ingalls R. R., Arnaout M. A. & Golenbock D. T. Outside-in signaling by lipopolysaccharide through a tailless integrin. J. Immunol. 159, 433–438 (1997 ).

    Not in our library

17. 17.

    Flo T. H. et al. Involvement of CD14 and beta2-integrins in activating cells with soluble and particulate lipopolysaccharides and mannuronic acid polymers. Infect. Immun. 68, 6770–6776 (2000 ).

    Not in our library10.1128/iai.68.12.6770-6776.2000

18. 18.

    Scott M. J. & Billiar T. R. Beta2-integrin-induced p38 MAPK activation is a key mediator in the CD14/TLR4/MD2-dependent uptake of lipopolysaccharide by hepatocytes. J. Biol. Chem. 283, 29433–29446 (2008 ).

    Not in our library10.1074/jbc.m803905200

19. 19.

    Perera P. Y. et al. CD11b/CD18 acts in concert with CD14 and Toll-like receptor (TLR) 4 to elicit full lipopolysaccharide and taxol-inducible gene expression. J. Immunol. 166, 574–581 (2001 ).

    Not in our library10.4049/jimmunol.166.1.574

20. 20.

    Taylor P. R. et al. A hierarchical role for classical pathway complement proteins in the clearance of apoptotic cells in vivo. J. Exp. Med. 192, 359–366 (2000 ).

    Not in our library10.1084/jem.192.3.359

21. 21.

    Coxon A. et al. A novel role for the beta 2 integrin CD11b/CD18 in neutrophil apoptosis: a homeostatic mechanism in inflammation. Immunity 5, 653–666 (1996 ).

    Not in our library10.1016/s1074-7613(00)80278-2

22. 22.

    Cao C., Lawrence D. A., Strickland D. K. & Zhang L. A specific role of integrin Mac-1 in accelerated macrophage efflux to the lymphatics. Blood 106, 3234–3241 (2005 ).

    Not in our library10.1182/blood-2005-03-1288

23. 23.

    Lacey D. C. et al. Defining GM-CSF- and macrophage-CSF-dependent macrophage responses by in vitro models. J. Immunol. 188, 5752–5765 (2012 ).

    Not in our library10.4049/jimmunol.1103426

24. 24.

    Krausgruber T. et al. IRF5 promotes inflammatory macrophage polarization and TH1-TH17 responses. Nat. Immunol. 12, 231–238 (2011 ).

    Not in our library10.1038/ni.1990

25. 25.

    Inaba K. et al. Generation of large numbers of dendritic cells from mouse bone marrow cultures supplemented with granulocyte/macrophage colony-stimulating factor. J. Exp. Med. 176, 1693–1702 (1992 ).

    Not in our library10.1084/jem.176.6.1693

26. 26.

    Rosas M. et al. The induction of inflammation by dectin-1 in vivo is dependent on myeloid cell programming and the progression of phagocytosis. J. Immunol. 181, 3549–3557 (2008 ).

    Not in our library10.4049/jimmunol.181.5.3549

27. 27.

    Wright S. D., Levin S. M., Jong M. T., Chad Z. & Kabbash L. G. CR3 (CD11b/CD18) expresses one binding site for Arg-Gly-Asp-containing peptides and a second site for bacterial lipopolysaccharide. J. Exp. Med. 169, 175–183 (1989 ).

    Not in our library10.1084/jem.169.1.175

28. 28.

    Akashi S. et al. Lipopolysaccharide interaction with cell surface Toll-like receptor 4-MD-2: higher affinity than that with MD-2 or CD14. J. Exp. Med. 198, 1035–1042 (2003 ).

    Not in our library10.1084/jem.20031076

29. 29.

    Hoebe K. et al. Upregulation of costimulatory molecules induced by lipopolysaccharide and double-stranded RNA occurs by Trif-dependent and Trif-independent pathways. Nat. Immunol. 4, 1223–1229 (2003 ).

    Not in our library10.1038/ni1010

30. 30.

    Blasius A. L. & Beutler B. Intracellular toll-like receptors. Immunity 32, 305–315 (2010 ).

    Not in our library10.1016/j.immuni.2010.03.012

31. 31.

    Jones S. C., Brahmakshatriya V., Huston G., Dibble J. & Swain S. L. TLR-activated dendritic cells enhance the response of aged naive CD4 T cells via an IL-6-dependent mechanism. J. Immunol. 185, 6783–6794 (2010 ).

    Not in our library10.4049/jimmunol.0901296

32. 32.

    Chai J. G., James E., Dewchand H., Simpson E. & Scott D. Transplantation tolerance induced by intranasal administration of HY peptides. Blood 103, 3951–3959 (2004 ).

    Not in our library10.1182/blood-2003-11-3763

33. 33.

    Derbyshire K. et al. Molecular mechanisms of induction of antigen-specific allograft tolerance by intranasal peptide administration. J. Immunol. 186, 5719–5728 (2011 ).

    Not in our library10.4049/jimmunol.1002444

34. 34.

    Lantz O., Grandjean I., Matzinger P. & Di Santo J. P. Gamma chain required for naive CD4+ T cell survival but not for antigen proliferation. Nat. Immunol. 1, 54–58 (2000 ).

    Not in our library10.1038/76917

35. 35.

    Shimazu R. et al. MD-2, a molecule that confers lipopolysaccharide responsiveness on Toll-like receptor 4. J. Exp. Med. 189, 1777–1782 (1999 ).

    Not in our library10.1084/jem.189.11.1777

36. 36.

    Triantafilou K., Triantafilou M. & Dedrick R. L. A CD14-independent LPS receptor cluster. Nat. Immunol. 2, 338–345 (2001 ).

    Not in our library10.1038/86342

37. 37.

    Aksoy E. et al. The p110delta isoform of the kinase PI(3)K controls the subcellular compartmentalization of TLR4 signaling and protects from endotoxic shock. Nat. Immunol. 13, 1045–1054 (2012 ).

    Not in our library10.1038/ni.2426

38. 38.

    Bullard D. C. et al. Critical requirement of CD11b (Mac-1) on T cells and accessory cells for development of experimental autoimmune encephalomyelitis. J. Immunol. 175, 6327–6333 (2005 ).

    Not in our library10.4049/jimmunol.175.10.6327

39. 39.

    Shimizu K. et al. Leukocyte integrin Mac-1 promotes acute cardiac allograft rejection. Circulation 117, 1997–2008 (2008 ).

    Not in our library10.1161/circulationaha.107.724310

40. 40.

    Ehirchiou D. et al. CD11b facilitates the development of peripheral tolerance by suppressing Th17 differentiation. J. Exp. Med. 204, 1519–1524 (2007 ).

    Not in our library10.1084/jem.20062292

41. 41.

    Ivashkiv L. B. Cross-regulation of signaling by ITAM-associated receptors. Nat. Immunol. 10, 340–347 (2009 ).

    Not in our library10.1038/ni.1706

42. 42.

    Lapilla M. et al. Histamine regulates autoreactive T cell activation and adhesiveness in inflamed brain microcirculation. J. Leukoc. Biol. 89, 259–267 (2011 ).

    Not in our library10.1189/jlb.0910486

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