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Accessory molecules for Toll-like receptors and their function

Key Points

  • Toll-like receptors (TLRs) are type I transmembrane proteins that are involved in innate and adaptive immune responses to pathogens and are found on the surface of cells and in endosomal compartments. Humans have ten functional TLRs, whereas mice express twelve.

  • The activation and function of both surface and endosomal TLRs depend on TLR accessory proteins. TLR accessory proteins can be involved in ligand delivery or recognition, or can function as endoplasmic reticulum (ER) chaperones or as trafficking or processing factors.

  • LPS-binding protein, MD2, CD36 and CD14 all participate in ligand recognition for surface TLRs. Progranulin, CD14, HMGB1 and LL37 aid in ligand delivery and recognition for endosomal TLRs.

  • The ER chaperones GRP94 and PRAT4A work together to allow for proper TLR folding and assembly. Delivery of endosomal TLRs from the ER to endolysosomes involves the scaffolding and trafficking factor UNC93B1; adaptor protein 3 is required for the translocation of TLR9 to lysosomes or lysosome-related organelles in bone marrow-derived macrophages.

  • Cathepsins and asparagine endopeptidase are proteases required for the cleavage and activation of endosomal TLRs.

  • The study of TLR cofactor function has contributed to a better understanding of TLR signalling pathways and innate and adaptive immunity.

Abstract

Toll-like receptors (TLRs) are essential components of the innate immune system. Accessory proteins are required for the biosynthesis and activation of TLRs. Here, we summarize recent findings on TLR accessory proteins that are required for cell-surface and endosomal TLR function, and we classify these proteins based on their function as ligand-recognition and delivery cofactors, chaperones and trafficking proteins. Because of their essential roles in TLR function, targeting of such accessory proteins may benefit strategies aimed at manipulating TLR activation for therapeutic applications.

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Figure 1: Accessory molecules mediate ligand binding and delivery to surface and endosomal TLRs.
Figure 2: ER chaperones and trafficking and processing factors for TLRs.

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References

  1. Janeway, C. A. Jr & Medzhitov, R. Introduction: the role of innate immunity in the adaptive immune response. Semin. Immunol. 10, 349–350 (1998).

    Article  PubMed  Google Scholar 

  2. Bianchi, M. E. DAMPs, PAMPs and alarmins: all we need to know about danger. J. Leukoc. Biol. 81, 1–5 (2007).

    Article  CAS  PubMed  Google Scholar 

  3. Kang, J. Y. & Lee, J.-O. Structural biology of the Toll-like receptor family. Annu. Rev. Biochem. 80, 917–941 (2011).

    Article  CAS  PubMed  Google Scholar 

  4. Kawai, T. & Akira, S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nature Immunol. 11, 373–384 (2010).

    Article  CAS  Google Scholar 

  5. O'Neill, L. A. & Bowie, A. G. The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling. Nature Rev. Immunol. 7, 353–364 (2007).

    CAS  Google Scholar 

  6. Trinchieri, G. & Sher, A. Cooperation of Toll-like receptor signals in innate immune defence. Nature Rev. Immunol. 7, 179–190 (2007).

    CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  8. Schroder, K. & Tschopp, J. The inflammasomes. Cell 140, 821–832 (2010).

    Article  CAS  PubMed  Google Scholar 

  9. Takeuchi, O. & Akira, S. Pattern recognition receptors and inflammation. Cell 140, 805–820 (2010).

    Article  CAS  PubMed  Google Scholar 

  10. Ting, J. P., Duncan, J. A. & Lei, Y. How the noninflammasome NLRs function in the innate immune system. Science 327, 286–290 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Tschopp, J. & Schroder, K. NLRP3 inflammasome activation: the convergence of multiple signalling pathways on ROS production? Nature Rev. Immunol. 10, 210–215 (2010).

    Article  CAS  Google Scholar 

  12. Ulevitch, R. J. & Tobias, P. S. Receptor-dependent mechanisms of cell stimulation by bacterial endotoxin. Annu. Rev. Immunol. 13, 437–457 (1995).

    Article  CAS  PubMed  Google Scholar 

  13. Jiang, Z. et al. CD14 is required for MyD88-independent LPS signaling. Nature Immunol. 6, 565–570 (2005).

    Article  CAS  Google Scholar 

  14. Dziarski, R., Tapping, R. I. & Tobias, P. S. Binding of bacterial peptidoglycan to CD14. J. Biol. Chem. 273, 8680–8690 (1998).

    Article  CAS  PubMed  Google Scholar 

  15. Schroder, N. W. et al. Lipopolysaccharide binding protein binds to triacylated and diacylated lipopeptides and mediates innate immune responses. J. Immunol. 173, 2683–2691 (2004).

    Article  PubMed  Google Scholar 

  16. Schroder, N. W. et al. Lipoteichoic acid (LTA) of Streptococcus pneumoniae and Staphylococcus aureus activates immune cells via Toll-like receptor (TLR)-2, lipopolysaccharide-binding protein (LBP), and CD14, whereas TLR-4 and MD-2 are not involved. J. Biol. Chem. 278, 15587–15594 (2003).

    Article  PubMed  Google Scholar 

  17. Jack, R. S. et al. Lipopolysaccharide-binding protein is required to combat a murine Gram-negative bacterial infection. Nature 389, 742–745 (1997).

    Article  CAS  PubMed  Google Scholar 

  18. Weber, J. R. et al. Recognition of pneumococcal peptidoglycan: an expanded, pivotal role for LPS binding protein. Immunity 19, 269–279 (2003).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Nagai, Y. et al. Essential role of MD-2 in LPS responsiveness and TLR4 distribution. Nature Immunol. 3, 667–672 (2002).

    Article  CAS  Google Scholar 

  21. Park, B. S. et al. The structural basis of lipopolysaccharide recognition by the TLR4–MD-2 complex. Nature 458, 1191–1195 (2009). This paper is the first description of the crystal structure of a TLR in complex with its ligand and an accessory molecule.

    Article  CAS  PubMed  Google Scholar 

  22. Calvo, D., Dopazo, J. & Vega, M. A. The CD36, CLA-1 (CD36L1), and LIMPII (CD36L2) gene family: cellular distribution, chromosomal location, and genetic evolution. Genomics 25, 100–106 (1995).

    Article  CAS  PubMed  Google Scholar 

  23. Triantafilou, M. et al. Membrane sorting of Toll-like receptor (TLR)-2/6 and TLR2/1 heterodimers at the cell surface determines heterotypic associations with CD36 and intracellular targeting. J. Biol. Chem. 281, 31002–31011 (2006).

    Article  CAS  PubMed  Google Scholar 

  24. Hoebe, K. et al. CD36 is a sensor of diacylglycerides. Nature 433, 523–527 (2005).

    Article  CAS  PubMed  Google Scholar 

  25. Stuart, L. M. et al. Response to Staphylococcus aureus requires CD36-mediated phagocytosis triggered by the COOH-terminal cytoplasmic domain. J. Cell Biol. 170, 477–485 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Stewart, C. R. et al. CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer. Nature Immunol. 11, 155–161 (2010).

    Article  CAS  Google Scholar 

  27. Tao, N., Wagner, S. J. & Lublin, D. M. CD36 is palmitoylated on both N- and C-terminal cytoplasmic tails. J. Biol. Chem. 271, 22315–22320 (1996).

    Article  CAS  PubMed  Google Scholar 

  28. Baumann, C. L. et al. CD14 is a coreceptor of Toll-like receptors 7 and 9. J. Exp. Med. 207, 2689–2701 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Hailman, E. et al. Lipopolysaccharide (LPS)-binding protein accelerates the binding of LPS to CD14. J. Exp. Med. 179, 269–277 (1994).

    Article  CAS  PubMed  Google Scholar 

  30. Lee, H. K., Dunzendorfer, S., Soldau, K. & Tobias, P. S. Double-stranded RNA-mediated TLR3 activation is enhanced by CD14. Immunity 24, 153–163 (2006). This paper provided the first concrete evidence that CD14 is important for endosomal TLRs in addition to surface TLRs.

    Article  CAS  PubMed  Google Scholar 

  31. Nakata, T. et al. CD14 directly binds to triacylated lipopeptides and facilitates recognition of the lipopeptides by the receptor complex of Toll-like receptors 2 and 1 without binding to the complex. Cell. Microbiol. 8, 1899–1909 (2006).

    Article  CAS  PubMed  Google Scholar 

  32. Kim, J. I. et al. Crystal structure of CD14 and its implications for lipopolysaccharide signaling. J. Biol. Chem. 280, 11347–11351 (2005).

    Article  CAS  PubMed  Google Scholar 

  33. Haziot, A. et al. Resistance to endotoxin shock and reduced dissemination of Gram-negative bacteria in CD14-deficient mice. Immunity 4, 407–414 (1996).

    Article  CAS  PubMed  Google Scholar 

  34. Zanoni, I. et al. CD14 controls the LPS-induced endocytosis of Toll-like receptor 4. Cell 147, 868–880 (2011). This was the first description of LPS-induced trafficking of TLR4 by CD14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Akashi-Takamura, S. & Miyake, K. TLR accessory molecules. Curr. Opin. Immunol. 20, 420–425 (2008).

    Article  CAS  PubMed  Google Scholar 

  36. da Silva Correia, J., Soldau, K., Christen, U., Tobias, P. S. & Ulevitch, R. J. Lipopolysaccharide is in close proximity to each of the proteins in its membrane receptor complex: transfer from CD14 to TLR4 and MD-2. J. Biol. Chem. 276, 21129–21135 (2001).

    Article  CAS  PubMed  Google Scholar 

  37. Gioannini, T. L. et al. Isolation of an endotoxin–MD-2 complex that produces Toll-like receptor 4-dependent cell activation at picomolar concentrations. Proc. Natl Acad. Sci. USA 101, 4186–4191 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Compton, T. et al. Human cytomegalovirus activates inflammatory cytokine responses via CD14 and Toll-like receptor 2. J. Virol. 77, 4588–4596 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Georgel, P. et al. Vesicular stomatitis virus glycoprotein G activates a specific antiviral Toll-like receptor 4-dependent pathway. Virology 362, 304–313 (2007).

    Article  CAS  PubMed  Google Scholar 

  40. Kurt-Jones, E. A. et al. Pattern recognition receptors TLR4 and CD14 mediate response to respiratory syncytial virus. Nature Immunol. 1, 398–401 (2000).

    Article  CAS  Google Scholar 

  41. Carpenter, S. et al. TRIL, a functional component of the TLR4 signaling complex, highly expressed in brain. J. Immunol. 183, 3989–3995 (2009).

    Article  CAS  PubMed  Google Scholar 

  42. Carpenter, S., Wochal, P., Dunne, A. & O'Neill, L. A. Toll-like receptor 3 (TLR3) signaling requires TLR4 interactor with leucine-rich repeats (TRIL). J. Biol. Chem. 286, 38795–38804 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Kessenbrock, K. et al. Proteinase 3 and neutrophil elastase enhance inflammation in mice by inactivating antiinflammatory progranulin. J. Clin. Invest. 118, 2438–2447 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Zhu, J. et al. Conversion of proepithelin to epithelins: roles of SLPI and elastase in host defense and wound repair. Cell 111, 867–878 (2002).

    Article  CAS  PubMed  Google Scholar 

  45. Park, B. et al. Granulin is a soluble cofactor for Toll-like receptor 9 signaling. Immunity 34, 505–513 (2011). Here, granulin was shown to have an essential role in ligand delivery for TLR9 activation.

    Article  PubMed  CAS  Google Scholar 

  46. Lotze, M. T. & Tracey, K. J. High-mobility group box 1 protein (HMGB1): nuclear weapon in the immune arsenal. Nature Rev. Immunol. 5, 331–342 (2005).

    Article  CAS  Google Scholar 

  47. Andersson, U. & Tracey, K. J. HMGB1 is a therapeutic target for sterile inflammation and infection. Annu. Rev. Immunol. 29, 139–162 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Ivanov, S. et al. A novel role for HMGB1 in TLR9-mediated inflammatory responses to CpG-DNA. Blood 110, 1970–1981 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Tian, J. et al. Toll-like receptor 9-dependent activation by DNA-containing immune complexes is mediated by HMGB1 and RAGE. Nature Immunol. 8, 487–496 (2007). This work first reported a role for HMGB1 in delivering DNA to TLR9.

    Article  CAS  Google Scholar 

  50. Urbonaviciute, V. et al. Induction of inflammatory and immune responses by HMGB1–nucleosome complexes: implications for the pathogenesis of SLE. J. Exp. Med. 205, 3007–3018 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Leadbetter, E. A. et al. Chromatin–IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors. Nature 416, 603–607 (2002).

    Article  CAS  PubMed  Google Scholar 

  52. Avalos, A. M. et al. RAGE-independent autoreactive B cell activation in response to chromatin and HMGB1/DNA immune complexes. Autoimmunity 43, 103–110 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Yanai, H. et al. HMGB proteins function as universal sentinels for nucleic-acid-mediated innate immune responses. Nature 462, 99–103 (2009).

    Article  CAS  PubMed  Google Scholar 

  54. Lande, R. et al. Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide. Nature 449, 564–569 (2007). This paper demonstrated the role of LL37 in DNA delivery to TLR9 in pDCs.

    Article  CAS  PubMed  Google Scholar 

  55. Gilliet, M. & Lande, R. Antimicrobial peptides and self-DNA in autoimmune skin inflammation. Curr. Opin. Immunol. 20, 401–407 (2008).

    CAS  PubMed  Google Scholar 

  56. Zanetti, M., Gennaro, R. & Romeo, D. The cathelicidin family of antimicrobial peptide precursors: a component of the oxygen-independent defense mechanisms of neutrophils. Ann. NY Acad. Sci. 832, 147–162 (1997).

    Article  CAS  PubMed  Google Scholar 

  57. Ganguly, D. et al. Self-RNA–antimicrobial peptide complexes activate human dendritic cells through TLR7 and TLR8. J. Exp. Med. 206, 1983–1994 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Yang, Y. & Li, Z. Roles of heat shock protein gp96 in the ER quality control: redundant or unique function? Mol. Cells 20, 173–182 (2005).

    Article  CAS  PubMed  Google Scholar 

  59. Liu, B. & Li, Z. Endoplasmic reticulum HSP90b1 (gp96, grp94) optimizes B-cell function via chaperoning integrin and TLR but not immunoglobulin. Blood 112, 1223–1230 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Randow, F. & Seed, B. Endoplasmic reticulum chaperone gp96 is required for innate immunity but not cell viability. Nature Cell Biol. 3, 891–896 (2001).

    Article  CAS  PubMed  Google Scholar 

  61. Wanderling, S. et al. GRP94 is essential for mesoderm induction and muscle development because it regulates insulin-like growth factor secretion. Mol. Biol. Cell 18, 3764–3775 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Yang, Y. et al. Heat shock protein gp96 is a master chaperone for Toll-like receptors and is important in the innate function of macrophages. Immunity 26, 215–226 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Staron, M. et al. Heat-shock protein gp96/grp94 is an essential chaperone for the platelet glycoprotein Ib-IX-V complex. Blood 117, 7136–7144 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Liu, B. et al. Folding of Toll-like receptors by the HSP90 paralogue gp96 requires a substrate-specific cochaperone. Nature Commun. 1, 79 (2010). This paper shows that GRP94 and PRAT4A work together to chaperone TLRs.

    Article  CAS  Google Scholar 

  65. Wakabayashi, Y. et al. A protein associated with Toll-like receptor 4 (PRAT4A) regulates cell surface expression of TLR4. J. Immunol. 177, 1772–1779 (2006).

    Article  CAS  PubMed  Google Scholar 

  66. Takahashi, K. et al. A protein associated with Toll-like receptor (TLR) 4 (PRAT4A) is required for TLR-dependent immune responses. J. Exp. Med. 204, 2963–2976 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Kiyokawa, T. et al. A single base mutation in the PRAT4A gene reveals differential interaction of PRAT4A with Toll-like receptors. Int. Immunol. 20, 1407–1415 (2008).

    Article  CAS  PubMed  Google Scholar 

  68. Tabeta, K. et al. The Unc93b1 mutation 3d disrupts exogenous antigen presentation and signaling via Toll-like receptors 3, 7 and 9. Nature Immunol. 7, 156–164 (2006).

    Article  CAS  Google Scholar 

  69. Casrouge, A. et al. Herpes simplex virus encephalitis in human UNC-93B deficiency. Science 314, 308–312 (2006).

    Article  CAS  PubMed  Google Scholar 

  70. Brinkmann, M. M. et al. The interaction between the ER membrane protein UNC93B and TLR3, 7, and 9 is crucial for TLR signaling. J. Cell Biol. 177, 265–275 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Kim, Y. M., Brinkmann, M. M., Paquet, M. E. & Ploegh, H. L. UNC93B1 delivers nucleotide-sensing Toll-like receptors to endolysosomes. Nature 452, 234–238 (2008). This paper provides evidence for the role of UNC93B1 in the trafficking of endosomal TLRs.

    Article  CAS  PubMed  Google Scholar 

  72. Fukui, R. et al. Unc93B1 biases Toll-like receptor responses to nucleic acid in dendritic cells toward DNA- but against RNA-sensing. J. Exp. Med. 206, 1339–1350 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Fukui, R. et al. Unc93B1 restricts systemic lethal inflammation by orchestrating Toll-like receptor 7 and 9 trafficking. Immunity 35, 69–81 (2011).

    Article  CAS  PubMed  Google Scholar 

  74. Nakatsu, F. & Ohno, H. Adaptor protein complexes as the key regulators of protein sorting in the post-Golgi network. Cell Struct. Funct. 28, 419–429 (2003).

    Article  CAS  PubMed  Google Scholar 

  75. Sasai, M., Linehan, M. M. & Iwasaki, A. Bifurcation of Toll-like receptor 9 signaling by adaptor protein 3. Science 329, 1530–1534 (2010). This study was the first to demonstrate that AP3 has a role in TLR9-dependent IFN responses.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Blasius, A. L. et al. Slc15a4, AP-3, and Hermansky-Pudlak syndrome proteins are required for Toll-like receptor signaling in plasmacytoid dendritic cells. Proc. Natl Acad. Sci. USA 107, 19973–19978 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Guiducci, C. et al. Properties regulating the nature of the plasmacytoid dendritic cell response to Toll-like receptor 9 activation. J. Exp. Med. 203, 1999–2008 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Honda, K. et al. Spatiotemporal regulation of MyD88–IRF-7 signalling for robust type-I interferon induction. Nature 434, 1035–1040 (2005).

    Article  CAS  PubMed  Google Scholar 

  79. Ewald, S. E. et al. The ectodomain of Toll-like receptor 9 is cleaved to generate a functional receptor. Nature 456, 658–662 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Park, B. et al. Proteolytic cleavage in an endolysosomal compartment is required for activation of Toll-like receptor 9. Nature Immunol. 9, 1407–1414 (2008). References 79 and 80 demonstrate the cleavage requirement for TLR9 activation by CpG DNA.

    Article  CAS  Google Scholar 

  81. Asagiri, M. et al. Cathepsin K-dependent Toll-like receptor 9 signaling revealed in experimental arthritis. Science 319, 624–627 (2008).

    Article  CAS  PubMed  Google Scholar 

  82. Matsumoto, F. et al. Cathepsins are required for Toll-like receptor 9 responses. Biochem. Biophys. Res. Commun. 367, 693–699 (2008).

    Article  CAS  PubMed  Google Scholar 

  83. Sepulveda, F. E. et al. Critical role for asparagine endopeptidase in endocytic Toll-like receptor signaling in dendritic cells. Immunity 31, 737–748 (2009). This is the first demonstration of a role for AEP in TLR9 activation in primary DCs.

    Article  CAS  PubMed  Google Scholar 

  84. Ewald, S. E. et al. Nucleic acid recognition by Toll-like receptors is coupled to stepwise processing by cathepsins and asparagine endopeptidase. J. Exp. Med. 208, 643–651 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Saitoh, T. et al. Antiviral protein Viperin promotes Toll-like receptor 7- and Toll-like receptor 9-mediated type I interferon production in plasmacytoid dendritic cells. Immunity 34, 352–363 (2011).

    Article  CAS  PubMed  Google Scholar 

  86. Gerold, G. et al. A Toll-like receptor 2–integrin β3 complex senses bacterial lipopeptides via vitronectin. Nature Immunol. 9, 761–768 (2008).

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  88. 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 

  89. Nagai, Y. et al. The radioprotective 105/MD-1 complex links TLR2 and TLR4/MD-2 in antibody response to microbial membranes. J. Immunol. 174, 7043–7049 (2005).

    Article  CAS  PubMed  Google Scholar 

  90. Divanovic, S. et al. Negative regulation of Toll-like receptor 4 signaling by the Toll-like receptor homolog RP105. Nature Immunol. 6, 571–578 (2005).

    Article  CAS  Google Scholar 

  91. Blumenthal, A. et al. RP105 facilitates macrophage activation by Mycobacterium tuberculosis lipoproteins. Cell Host Microbe 5, 35–46 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Uccellini, M. B. et al. Autoreactive B cells discriminate CpG-rich and CpG-poor DNA and this response is modulated by IFN-α. J. Immunol. 181, 5875–5884 (2008).

    Article  CAS  PubMed  Google Scholar 

  93. Viglianti, G. A. et al. Activation of autoreactive B cells by CpG dsDNA. Immunity 19, 837–847 (2003).

    Article  CAS  PubMed  Google Scholar 

  94. Lau, C. M. et al. RNA-associated autoantigens activate B cells by combined B cell antigen receptor/Toll-like receptor 7 engagement. J. Exp. Med. 202, 1171–1177 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Chaturvedi, A., Dorward, D. & Pierce, S. K. The B cell receptor governs the subcellular location of Toll-like receptor 9 leading to hyperresponses to DNA-containing antigens. Immunity 28, 799–809 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Avalos, A. M. et al. Differential cytokine production and bystander activation of autoreactive B cells in response to CpG-A and CpG-B oligonucleotides. J. Immunol. 183, 6262–6268 (2009).

    Article  CAS  PubMed  Google Scholar 

  97. Hori, O. et al. The receptor for advanced glycation end products (RAGE) is a cellular binding site for amphoterin. Mediation of neurite outgrowth and co-expression of rage and amphoterin in the developing nervous system. J. Biol. Chem. 270, 25752–25761 (1995).

    Article  CAS  PubMed  Google Scholar 

  98. Bierhaus, A. et al. Understanding RAGE, the receptor for advanced glycation end products. J. Mol. Med. 83, 876–886 (2005).

    Article  CAS  PubMed  Google Scholar 

  99. Boullier, A. et al. The binding of oxidized low density lipoprotein to mouse CD36 is mediated in part by oxidized phospholipids that are associated with both the lipid and protein moieties of the lipoprotein. J. Biol. Chem. 275, 9163–9169 (2000).

    Article  CAS  PubMed  Google Scholar 

  100. Coraci, I. S. et al. CD36, a class B scavenger receptor, is expressed on microglia in Alzheimer's disease brains and can mediate production of reactive oxygen species in response to β-amyloid fibrils. Am. J. Pathol. 160, 101–112 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Jimenez-Dalmaroni, M. J. et al. Soluble CD36 ectodomain binds negatively charged diacylglycerol ligands and acts as a co-receptor for TLR2. PLoS ONE 4, e7411 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. Yang, R. B., Mark, M. R., Gurney, A. L. & Godowski, P. J. Signaling events induced by lipopolysaccharide-activated Toll-like receptor 2. J. Immunol. 163, 639–643 (1999).

    CAS  PubMed  Google Scholar 

  103. Muta, T. & Takeshige, K. Essential roles of CD14 and lipopolysaccharide-binding protein for activation of Toll-like receptor (TLR)2 as well as TLR4 reconstitution of TLR2- and TLR4-activation by distinguishable ligands in LPS preparations. Eur. J. Biochem. 268, 4580–4589 (2001).

    Article  CAS  PubMed  Google Scholar 

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We thank M. M. Brinkmann and Y.-M. Kim for critical reading of the manuscript.

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Glossary

Alarmins

Endogenous mediators that are released by necrotic cells in response to infection or injury and that interact with pattern-recognition receptors to activate innate immune cells.

Acute-phase protein

A member of a group of proteins — including C-reactive protein, serum amyloid A, fibrinogen and α1-acid glycoprotein — that are secreted into the blood in increased or decreased quantities by hepatocytes in response to trauma, inflammation or disease. These proteins can be inhibitors or mediators of inflammatory processes.

Lipid rafts

Structures that are proposed to arise from phase separation of different plasma membrane lipids as a result of the selective coalescence of certain lipids on the basis of their physical properties. This results in the formation of distinct and stable lipid domains in membranes that might provide a platform for membrane-associated protein organization.

Sterile inflammation

An inflammatory response triggered by tissue damage in the absence of infection.

Amphipathic peptide

A peptide that contains hydrophilic and hydrophobic domains, which allow the peptide to interact both with charged residues and with lipophilic structures.

Endosomes

Vesicles of the endocytic pathway that transport proteins from the plasma membrane and the Golgi compartment and have a mildly acidic pH.

Paralogue

A homologous gene that resulted from a gene duplication event.

Small hairpin RNA

One of the two most common forms of short (usually 21-base-pairs long) double-stranded RNAs used for gene silencing. The other form is known as small interfering RNA (siRNA).

Lysosomes

Organelles involved in protein degradation that have a low pH and correspond to the last step of the endocytic pathway.

Lysosome-related organelles

(LROs). Cell type-specific compartments that share properties with lysosomes but have specialized functions. LROs include melanosomes, lytic granules, MHC class II compartments, platelet-dense granules, basophil granules and azurophil granules.

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Lee, C., Avalos, A. & Ploegh, H. Accessory molecules for Toll-like receptors and their function. Nat Rev Immunol 12, 168–179 (2012). https://doi.org/10.1038/nri3151

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