Below the surface: The inner lives of TLR4 and TLR9

Abstract

TLRs are a class of pattern recognition receptors (PRRs) that detect invading microbes by recognizing pathogen-associated molecular patterns (PAMPs). Upon PAMP engagement, TLRs activate a signaling cascade that leads to the production of inflammatory mediators. The localization of TLRs, either on the plasma membrane or in the endolysosomal compartment, has been considered to be a fundamental aspect to determine to which ligands the receptors bind, and which transduction pathways are induced. However, new observations have challenged this view by identifying complex trafficking events that occur upon TLR-ligand binding. These findings have highlighted the central role that endocytosis and receptor trafficking play in the regulation of the innate immune response. Here, we review the TLR4 and TLR9 transduction pathways and the importance of their different subcellular localization during the inflammatory response. Finally, we discuss the implications of TLR9 subcellular localization in autoimmunity.

Shown for reading. Its publisher allows quoting it, not republishing it.

References 172

1. 1.

   Janeway CA, Jr. Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harb Symp Quant Biol. 1989;54(Pt 1):1‐13.

   Not in our library10.1101/sqb.1989.054.01.003

2. 2.

   Joffre O, Nolte MA, Sporri R, Reis e Sousa C. Inflammatory signals in dendritic cell activation and the induction of adaptive immunity. Immunol Rev. 2009;227:234‐247.

   Not in our library10.1111/j.1600-065x.2008.00718.x

3. 3.

   Fox RI, Kang HI. Pathogenesis of Sjogren's syndrome. Rheum Dis Clin North Am. 1992;18:517‐538.

   Not in our library

4. 4.

   Christensen SR, Shupe J, Nickerson K, Kashgarian M, Flavell RA, Shlomchik MJ. Toll‐like receptor 7 and TLR9 dictate autoantibody specificity and have opposing inflammatory and regulatory roles in a murine model of lupus. Immunity. 2006;25:417‐428.

   Not in our library10.1016/j.immuni.2006.07.013

5. 5.

   Krishnamoorthy G, Saxena A, Mars LT, et al. Myelin‐specific T cells also recognize neuronal autoantigen in a transgenic mouse model of multiple sclerosis. Nat Med. 2009;15:626‐632.

   Not in our library10.1038/nm.1975

6. 6.

   Ntelis K, Solomou EE, Sakkas L, Liossis SN, Daoussis D. The role of platelets in autoimmunity, vasculopathy, and fibrosis: implications for systemic sclerosis. Semin Arthritis Rheum. 2017;47:409‐417.

   Not in our library10.1016/j.semarthrit.2017.05.004

7. 7.

   Nielen MM, van Schaardenburg D, Reesink HW, et al. Specific autoantibodies precede the symptoms of rheumatoid arthritis: a study of serial measurements in blood donors. Arthritis Rheum. 2004;50:380‐386.

   Not in our library10.1002/art.20018

8. 8.

   Conrad C, Boyman O, Tonel G, et al. Alpha1beta1 integrin is crucial for accumulation of epidermal T cells and the development of psoriasis. Nat Med. 2007;13:836‐842.

   Not in our library10.1038/nm1605

9. 9.

   O'Neill LA, Golenbock D, Bowie AG. The history of Toll‐like receptors—redefining innate immunity. Nat Rev Immunol. 2013;13:453‐460.

   Not in our library10.1038/nri3446

10. 10.

    Bell JK, Mullen GE, Leifer CA, Mazzoni A, Davies DR, Segal DM. Leucine‐rich repeats and pathogen recognition in Toll‐like receptors. Trends Immunol. 2003;24:528‐533.

    Not in our library10.1016/s1471-4906(03)00242-4

11. 11.

    O'Neill LA, Bowie AG. The family of five: tIR‐domain‐containing adaptors in Toll‐like receptor signalling. Nat Rev Immunol. 2007;7:353‐364.

    Not in our library10.1038/nri2079

12. 12.

    Brubaker SW, Bonham KS, Zanoni I, Kagan JC. Innate immune pattern recognition: a cell biological perspective. Annu Rev Immunol. 2015;33:257‐290.

    Not in our library10.1146/annurev-immunol-032414-112240

13. 13.

    Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell. 2006;124:783‐801.

    Not in our library10.1016/j.cell.2006.02.015

14. 14.

    Zhang SY, Jouanguy E, Ugolini S, et al. TLR3 deficiency in patients with herpes simplex encephalitis. Science. 2007;317:1522‐1527.

    Not in our library10.1126/science.1139522

15. 15.

    Kleinman ME, Yamada K, Takeda A, et al. Sequence‐ and target‐independent angiogenesis suppression by siRNA via TLR3. Nature. 2008;452:591‐597.

    Not in our library10.1038/nature06765

16. 16.

    Bernard JJ, Cowing‐Zitron C, Nakatsuji T, et al. Ultraviolet radiation damages self noncoding RNA and is detected by TLR3. Nat Med. 2012;18:1286‐1290.

    Not in our library10.1038/nm.2861

17. 17.

    Mancuso G, Gambuzza M, Midiri A, et al. Bacterial recognition by TLR7 in the lysosomes of conventional dendritic cells. Nat Immunol. 2009;10:587‐594.

    Not in our library10.1038/ni.1733

18. 18.

    Guiducci C, Gong M, Cepika AM, et al. RNA recognition by human TLR8 can lead to autoimmune inflammation. J Exp Med. 2013;210:2903‐2919.

    Not in our library10.1084/jem.20131044

19. 19.

    Forsbach A, Nemorin JG, Montino C, et al. Identification of RNA sequence motifs stimulating sequence‐specific TLR8‐dependent immune responses. J Immunol. 2008;180:3729‐3738.

    Not in our library10.4049/jimmunol.180.6.3729

20. 20.

    Coban C, Igari Y, Yagi M, et al. Immunogenicity of whole‐parasite vaccines against Plasmodium falciparum involves malarial hemozoin and host TLR9. Cell Host Microbe. 2010;7:50‐61.

    Not in our library10.1016/j.chom.2009.12.003

21. 21.

    Parroche P, Lauw FN, Goutagny N, et al. Malaria hemozoin is immunologically inert but radically enhances innate responses by presenting malaria DNA to Toll‐like receptor 9. Proc Natl Acad Sci U S A. 2007;104:1919‐1924.

    Not in our library10.1073/pnas.0608745104

22. 22.
    Sequence specific detection of bacterial 23S ribosomal RNA by TLR13 · 2012

    No notice
23. 23.

    Shi Z, Cai Z, Sanchez A, et al. A novel Toll‐like receptor that recognizes vesicular stomatitis virus. J Biol Chem. 2011;286:4517‐4524.

    Not in our library10.1074/jbc.m110.159590

24. 24.

    Mathur R, Oh H, Zhang D, et al. A mouse model of Salmonella typhi infection. Cell. 2012;151:590‐602.

    Not in our library10.1016/j.cell.2012.08.042

25. 25.

    Yarovinsky F, Zhang D, Andersen JF, et al. TLR11 activation of dendritic cells by a protozoan profilin‐like protein. Science. 2005;308:1626‐1629.

    Not in our library10.1126/science.1109893

26. 26.

    Koblansky AA, Jankovic D, Oh H, et al. Recognition of profilin by Toll‐like receptor 12 is critical for host resistance to Toxoplasma gondii. Immunity. 2013;38:119‐130.

    Not in our library10.1016/j.immuni.2012.09.016

27. 27.

    Yamamoto M, Sato S, Hemmi H, et al. TRAM is specifically involved in the Toll‐like receptor 4‐mediated MyD88‐independent signaling pathway. Nat Immunol. 2003;4:1144‐1150.

    Not in our library10.1038/ni986

28. 28.

    Honda K, Yanai H, Negishi H, et al. IRF‐7 is the master regulator of type‐I interferon‐dependent immune responses. Nature. 2005;434:772‐777.

    Not in our library10.1038/nature03464

29. 29.

    Honda K, Ohba Y, Yanai H, et al. Spatiotemporal regulation of MyD88‐IRF‐7 signalling for robust type‐I interferon induction. Nature. 2005;434:1035‐1040.

    Not in our library10.1038/nature03547

30. 30.

    Kim YM, Brinkmann MM, Paquet ME, Ploegh HL. UNC93B1 delivers nucleotide‐sensing toll‐like receptors to endolysosomes. Nature. 2008;452:234‐238.

    Not in our library10.1038/nature06726

31. 31.
    UNC93B1 mediates differential trafficking of endosomal TLRs · 2013

    No notice
32. 32.

    Pelka K, Bertheloot D, Reimer E, et al. The chaperone UNC93B1 regulates Toll‐like receptor stability independently of endosomal TLR transport. Immunity. 2018;48:911‐922. e7.

    Not in our library10.1016/j.immuni.2018.04.011

33. 33.

    Yang Y, Liu B, Dai J, et al. Heat shock protein gp96 is a master chaperone for toll‐like receptors and is important in the innate function of macrophages. Immunity. 2007;26:215‐226.

    Not in our library10.1016/j.immuni.2006.12.005

34. 34.

    Takahashi K, Shibata T, Akashi‐Takamura S, et al. A protein associated with Toll‐like receptor (TLR) 4 (PRAT4A) is required for TLR‐dependent immune responses. J Exp Med. 2007;204:2963‐2976.

    Not in our library10.1084/jem.20071132

35. 35.

    Medzhitov R, Preston‐Hurlburt P. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature. 1997;388:394‐397.

    Not in our library10.1038/41131

36. 36.

    Kagan JC, Su T, Horng T, Chow A, Akira S, Medzhitov R. TRAM couples endocytosis of Toll‐like receptor 4 to the induction of interferon‐beta. Nat Immunol. 2008;9:361‐368.

    Not in our library10.1038/ni1569

37. 37.

    Brandt KJ, Fickentscher C, Kruithof EK, de Moerloose P. TLR2 ligands induce NF‐kappaB activation from endosomal compartments of human monocytes. PLoS One. 2013;8:e80743.

    Not in our library10.1371/journal.pone.0080743

38. 38.

    Barbalat R, Lau L, Locksley RM, Barton GM. Toll‐like receptor 2 on inflammatory monocytes induces type I interferon in response to viral but not bacterial ligands. Nat Immunol. 2009;10:1200‐1207.

    Not in our library10.1038/ni.1792

39. 39.

    Steimle A, Autenrieth IB, Frick JS. Structure and function: lipid A modifications in commensals and pathogens. Int J Med Microbiol. 2016;306:290‐301.

    Not in our library10.1016/j.ijmm.2016.03.001

40. 40.

    Rittig MG, Kaufmann A, Robins A, et al. Smooth and rough lipopolysaccharide phenotypes of Brucella induce different intracellular trafficking and cytokine/chemokine release in human monocytes. J Leukoc Biol. 2003;74:1045‐1055.

    Not in our library10.1189/jlb.0103015

Cited by papers we hold 2

• TLR Agonists as Mediators of Trained Immunity: Mechanistic Insight and Immunotherapeutic Potential to Combat Infection · 2021
  No notice
• TLR4 and CD14 trafficking and its influence on LPS-induced pro-inflammatory signaling · 2020
  No notice

Reads

A person counts once a day per paper. We keep no cookie and no address: a reader is a hash that changes every day. Any month under five reads shows no number.