Chapter 24 : Toll-Like Receptor Signaling and Its Inducible Proteins

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Toll-Like Receptor Signaling and Its Inducible Proteins, Page 1 of 2

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Various cell types, including macrophages, dendritic cells (DCs), neutrophils, natural killer cells, and fibroblasts, express Toll-like receptors (TLRs) that activate the immune system ( ). TLRs are type I transmembrane proteins with ectodomains containing leucine-rich repeats that mediate the recognition of pathogen-associated molecular patterns (PAMPs) derived from pathogens, and damage-associated molecular patterns (DAMPs) from dying or injured cells. TLRs harbor transmembrane domains and intracellular Toll–interleukin-1 (IL-1) receptor (TIR) domains in addition to leucine-rich repeat domains, and some adaptor molecules bind to them to activate the downstream signaling pathways. Various organisms express the TLR family, especially mammals, and 13 types of TLRs have been reported. TLR1 to -9 are conserved in both the mouse and human. However, in mice, a retroviral insertion has rendered the TLR10 molecule nonfunctional. TLR11, -12, and -13 do not occur in humans. The active TLRs localize differently. TLR1, -2, -4, -5, -6, and -10 are expressed on the cell surface, whereas TLR3, -7, -8, -9, -11, -12, and -13 are expressed in the endosome ( ). Studies of mice deficient in each TLR have shown that each TLR has a distinct function in terms of PAMP recognition and the immune responses.

Citation: Satoh T, Akira S. 2017. Toll-Like Receptor Signaling and Its Inducible Proteins, p 447-453. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0040-2016
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1. Akira S,, Uematsu S,, Takeuchi O . 2006. Pathogen recognition and innate immunity. Cell 124 : 783801.
2. Janeway CA Jr,, Medzhitov R . 2002. Innate immune recognition. Annu Rev Immunol 20 : 197216.
3. Celhar T,, Magalhães R,, Fairhurst AM . 2012. TLR7 and TLR9 in SLE: when sensing self goes wrong. Immunol Res 53 : 5877.
4. Kawai T,, Akira S . 2010. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol 11 : 373384.
5. Zanoni I,, Ostuni R,, Marek LR,, Barresi S,, Barbalat R,, Barton GM,, Granucci F,, Kagan JC . 2011. CD14 controls the LPS-induced endocytosis of Toll-like receptor 4. Cell 147 : 868880.
6. Vogl T,, Tenbrock K,, Ludwig S,, Leukert N,, Ehrhardt C,, van Zoelen MA,, Nacken W,, Foell D,, van der Poll T,, Sorg C,, Roth J . 2007. Mrp8 and Mrp14 are endogenous activators of Toll-like receptor 4, promoting lethal, endotoxin-induced shock. Nat Med 13 : 10421049.
7. Pouliot P,, Plante I,, Raquil MA,, Tessier PA,, Olivier M . 2008. Myeloid-related proteins rapidly modulate macrophage nitric oxide production during innate immune response. J Immunol 181 : 35953601.
8. Suganami T,, Mieda T,, Itoh M,, Shimoda Y,, Kamei Y,, Ogawa Y . 2007. Attenuation of obesity-induced adipose tissue inflammation in C3H/HeJ mice carrying a Toll-like receptor 4 mutation. Biochem Biophys Res Commun 354 : 4549.
9. Suganami T,, Tanimoto-Koyama K,, Nishida J,, Itoh M,, Yuan X,, Mizuarai S,, Kotani H,, Yamaoka S,, Miyake K,, Aoe S,, Kamei Y,, Ogawa Y . 2007. Role of the Toll-like receptor 4/NF-κB pathway in saturated fatty acid-induced inflammatory changes in the interaction between adipocytes and macrophages. Arterioscler Thromb Vasc Biol 27 : 8491.
10. Lin SC,, Lo YC,, Wu H . 2010. Helical assembly in the MyD88-IRAK4-IRAK2 complex in TLR/IL-1R signalling. Nature 465 : 885890.
11. Kollewe C,, Mackensen AC,, Neumann D,, Knop J,, Cao P,, Li S,, Wesche H,, Martin MU . 2004. Sequential autophosphorylation steps in the interleukin-1 receptor-associated kinase-1 regulate its availability as an adapter in interleukin-1 signaling. J Biol Chem 279 : 52275236.
12. Jiang Z,, Ninomiya-Tsuji J,, Qian Y,, Matsumoto K,, Li X . 2002. Interleukin-1 (IL-1) receptor-associated kinase-dependent IL-1-induced signaling complexes phosphorylate TAK1 and TAB2 at the plasma membrane and activate TAK1 in the cytosol. Mol Cell Biol 22 : 71587167.
13. Ajibade AA,, Wang HY,, Wang RF . 2013. Cell type-specific function of TAK1 in innate immune signaling. Trends Immunol 34 : 307316.
14. Chen ZJ . 2012. Ubiquitination in signaling to and activation of IKK. Immunol Rev 246 : 95106.
15. Jiang X,, Chen ZJ . 2011. The role of ubiquitylation in immune defence and pathogen evasion. Nat Rev Immunol 12 : 3548.
16. Chang M,, Jin W,, Sun SC . 2009. Peli1 facilitates TRIF-dependent Toll-like receptor signaling and proinflammatory cytokine production. Nat Immunol 10 : 10891095.
17. Kawasaki T,, Takemura N,, Standley DM,, Akira S,, Kawai T . 2013. The second messenger phosphatidylinositol-5-phosphate facilitates antiviral innate immune signaling. Cell Host Microbe 14 : 148158.
18. Blasius AL,, Beutler B . 2010. Intracellular Toll-like receptors. Immunity 32 : 305315.
19. Bernard JJ,, Cowing-Zitron C,, Nakatsuji T,, Muehleisen B,, Muto J,, Borkowski AW,, Martinez L,, Greidinger EL,, Yu BD,, Gallo RL . 2012. Ultraviolet radiation damages self noncoding RNA and is detected by TLR3. Nat Med 18 : 12861290.
20. Takemura N,, Kawasaki T,, Kunisawa J,, Sato S,, Lamichhane A,, Kobiyama K,, Aoshi T,, Ito J,, Mizuguchi K,, Karuppuchamy T,, Matsunaga K,, Miyatake S,, Mori N,, Tsujimura T,, Satoh T,, Kumagai Y,, Kawai T,, Standley DM,, Ishii KJ,, Kiyono H,, Akira S,, Uematsu S . 2014. Blockade of TLR3 protects mice from lethal radiation-induced gastrointestinal syndrome. Nat Commun 5 : 3492. doi:10.1038/ncomms4492.
21. Zhang SY,, Jouanguy E,, Ugolini S,, Smahi A,, Elain G,, Romero P,, Segal D,, Sancho-Shimizu V,, Lorenzo L,, Puel A,, Picard C,, Chapgier A,, Plancoulaine S,, Titeux M,, Cognet C,, von Bernuth H,, Ku CL,, Casrouge A,, Zhang XX,, Barreiro L,, Leonard J,, Hamilton C,, Lebon P,, Héron B,, Vallée L,, Quintana-Murci L,, Hovnanian A,, Rozenberg F,, Vivier E,, Geissmann F,, Tardieu M,, Abel L,, Casanova JL . 2007. TLR3 deficiency in patients with herpes simplex encephalitis. Science 317 : 15221527.
22. Mancuso G,, Gambuzza M,, Midiri A,, Biondo C,, Papasergi S,, Akira S,, Teti G,, Beninati C . 2009. Bacterial recognition by TLR7 in the lysosomes of conventional dendritic cells. Nat Immunol 10 : 587594.
23. Coban C,, Igari Y,, Yagi M,, Reimer T,, Koyama S,, Aoshi T,, Ohata K,, Tsukui T,, Takeshita F,, Sakurai K,, Ikegami T,, Nakagawa A,, Horii T,, Nuñez G,, Ishii KJ,, Akira S . 2010. Immunogenicity of whole-parasite vaccines against Plasmodium falciparum involves malarial hemozoin and host TLR9. Cell Host Microbe 7 : 5061.
24. Tabeta K,, Hoebe K,, Janssen EM,, Du X,, Georgel P,, Crozat K,, Mudd S,, Mann N,, Sovath S,, Goode J,, Shamel L,, Herskovits AA,, Portnoy DA,, Cooke M,, Tarantino LM,, Wiltshire T,, Steinberg BE,, Grinstein S,, Beutler B . 2006. The Unc93b1 mutation 3d disrupts exogenous antigen presentation and signaling via Toll-like receptors 3, 7 and 9. Nat Immunol 7 : 156164.
25. Hidmark A,, von Saint Paul A,, Dalpke AH . 2012. Cutting edge: TLR13 is a receptor for bacterial RNA. J Immunol 189 : 27172721.
26. Li XD,, Chen ZJ . 2012. Sequence specific detection of bacterial 23S ribosomal RNA by TLR13. eLife 1 : e00102. doi:10.7554/eLife.00102.
27. Oldenburg M,, Krüger A,, Ferstl R,, Kaufmann A,, Nees G,, Sigmund A,, Bathke B,, Lauterbach H,, Suter M,, Dreher S,, Koedel U,, Akira S,, Kawai T,, Buer J,, Wagner H,, Bauer S,, Hochrein H,, Kirschning CJ . 2012. TLR13 recognizes bacterial 23S rRNA devoid of erythromycin resistance-forming modification. Science 337 : 11111115.
28. Mathur R,, Oh H,, Zhang D,, Park SG,, Seo J,, Koblansky A,, Hayden MS,, Ghosh S . 2012. A mouse model of Salmonella Typhi infection. Cell 151 : 590602.
29. Yarovinsky F,, Zhang D,, Andersen JF,, Bannenberg GL,, Serhan CN,, Hayden MS,, Hieny S,, Sutterwala FS,, Flavell RA,, Ghosh S,, Sher A . 2005. TLR11 activation of dendritic cells by a protozoan profilin-like protein. Science 308 : 16261629.
30. Koblansky AA,, Jankovic D,, Oh H,, Hieny S,, Sungnak W,, Mathur R,, Hayden MS,, Akira S,, Sher A,, Ghosh S . 2013. Recognition of profilin by Toll-like receptor 12 is critical for host resistance to Toxoplasma gondii . Immunity 38 : 119130.
31. Andrade WA,, Souza MC,, Ramos-Martinez E,, Nagpal K,, Dutra MS,, Melo MB,, Bartholomeu DC,, Ghosh S,, Golenbock DT,, Gazzinelli RT . 2013. Combined action of nucleic acid-sensing Toll-like receptors and TLR11/TLR12 heterodimers imparts resistance to Toxoplasma gondii in mice. Cell Host Microbe 13 : 4253.
32. Broz P,, Monack DM . 2013. Newly described pattern recognition receptors team up against intracellular pathogens. Nat Rev Immunol 13 : 551565.
33. Matsushita K,, Takeuchi O,, Standley DM,, Kumagai Y,, Kawagoe T,, Miyake T,, Satoh T,, Kato H,, Tsujimura T,, Nakamura H,, Akira S . 2009. Zc3h12a is an RNase essential for controlling immune responses by regulating mRNA decay. Nature 458 : 11851190.
34. Kayama H,, Ramirez-Carrozzi VR,, Yamamoto M,, Mizutani T,, Kuwata H,, Iba H,, Matsumoto M,, Honda K,, Smale ST,, Takeda K . 2015. Class-specific regulation of pro-inflammatory genes by MyD88 pathways and IκBζ. J Biol Chem 290 : 22446.
35. Yamamoto M,, Yamazaki S,, Uematsu S,, Sato S,, Hemmi H,, Hoshino K,, Kaisho T,, Kuwata H,, Takeuchi O,, Takeshige K,, Saitoh T,, Yamaoka S,, Yamamoto N,, Yamamoto S,, Muta T,, Takeda K,, Akira S . 2004. Regulation of Toll/IL-1-receptor-mediated gene expression by the inducible nuclear protein IκBζ. Nature 430 : 218222.
36. Gilchrist M,, Thorsson V,, Li B,, Rust AG,, Korb M,, Roach JC,, Kennedy K,, Hai T,, Bolouri H,, Aderem A . 2006. Systems biology approaches identify ATF3 as a negative regulator of Toll-like receptor 4. Nature 441 : 173178.
37. Bours V,, Franzoso G,, Azarenko V,, Park S,, Kanno T,, Brown K,, Siebenlist U . 1993. The oncoprotein Bcl-3 directly transactivates through κB motifs via association with DNA-binding p50B homodimers. Cell 72 : 729739.
38. Kuwata H,, Matsumoto M,, Atarashi K,, Morishita H,, Hirotani T,, Koga R,, Takeda K . 2006. IκBNS inhibits induction of a subset of Toll-like receptor-dependent genes and limits inflammation. Immunity 24 : 4151.
39. Wessells J,, Baer M,, Young HA,, Claudio E,, Brown K,, Siebenlist U,, Johnson PF . 2004. BCL-3 and NF-κB p50 attenuate lipopolysaccharide-induced inflammatory responses in macrophages. J Biol Chem 279 : 4999550003.
40. Hirotani T,, Lee PY,, Kuwata H,, Yamamoto M,, Matsumoto M,, Kawase I,, Akira S,, Takeda K . 2005. The nuclear IκB protein IκBNS selectively inhibits lipopolysaccharide-induced IL-6 production in macrophages of the colonic lamina propria. J Immunol 174 : 36503657.
41. Iwasaki H,, Takeuchi O,, Teraguchi S,, Matsushita K,, Uehata T,, Kuniyoshi K,, Satoh T,, Saitoh T,, Matsushita M,, Standley DM,, Akira S . 2011. The IκB kinase complex regulates the stability of cytokine-encoding mRNA induced by TLR-IL-1R by controlling degradation of regnase-1. Nat Immunol 12 : 11671175.
42. Uehata T,, Iwasaki H,, Vandenbon A,, Matsushita K,, Hernandez-Cuellar E,, Kuniyoshi K,, Satoh T,, Mino T,, Suzuki Y,, Standley DM,, Tsujimura T,, Rakugi H,, Isaka Y,, Takeuchi O,, Akira S . 2013. Malt1-induced cleavage of regnase-1 in CD4+ helper T cells regulates immune activation. Cell 153 : 10361049.
43. Wagner BJ,, DeMaria CT,, Sun Y,, Wilson GM,, Brewer G . 1998. Structure and genomic organization of the human AUF1 gene: alternative pre-mRNA splicing generates four protein isoforms. Genomics 48 : 195202.
44. Carballo E,, Lai WS,, Blackshear PJ . 1998. Feedback inhibition of macrophage tumor necrosis factor-α production by tristetraprolin. Science 281 : 10011005.
45. Taylor GA,, Carballo E,, Lee DM,, Lai WS,, Thompson MJ,, Patel DD,, Schenkman DI,, Gilkeson GS,, Broxmeyer HE,, Haynes BF,, Blackshear PJ . 1996. A pathogenetic role for TNFα in the syndrome of cachexia, arthritis, and autoimmunity resulting from tristetraprolin (TTP) deficiency. Immunity 4 : 445454.
46. Glasmacher E,, Hoefig KP,, Vogel KU,, Rath N,, Du L,, Wolf C,, Kremmer E,, Wang X,, Heissmeyer V . 2010. Roquin binds inducible costimulator mRNA and effectors of mRNA decay to induce microRNA-independent post-transcriptional repression. Nat Immunol 11 : 725733.
47. Yu D,, Tan AH,, Hu X,, Athanasopoulos V,, Simpson N,, Silva DG,, Hutloff A,, Giles KM,, Leedman PJ,, Lam KP,, Goodnow CC,, Vinuesa CG . 2007. Roquin represses autoimmunity by limiting inducible T-cell co-stimulator messenger RNA. Nature 450 : 299303.
48. Chen CY,, Gherzi R,, Ong SE,, Chan EL,, Raijmakers R,, Pruijn GJ,, Stoecklin G,, Moroni C,, Mann M,, Karin M . 2001. AU binding proteins recruit the exosome to degrade ARE-containing mRNAs. Cell 107 : 451464.
49. Gherzi R,, Lee KY,, Briata P,, Wegmüller D,, Moroni C,, Karin M,, Chen CY . 2004. A KH domain RNA binding protein, KSRP, promotes ARE-directed mRNA turnover by recruiting the degradation machinery. Mol Cell 14 : 571583.
50. Agger K,, Cloos PA,, Christensen J,, Pasini D,, Rose S,, Rappsilber J,, Issaeva I,, Canaani E,, Salcini AE,, Helin K . 2007. UTX and JMJD3 are histone H3K27 demethylases involved in HOX gene regulation and development. Nature 449 : 731734.
51. De Santa F,, Totaro MG,, Prosperini E,, Notarbartolo S,, Testa G,, Natoli G . 2007. The histone H3 lysine-27 demethylase Jmjd3 links inflammation to inhibition of polycomb-mediated gene silencing. Cell 130 : 10831094.
52. Lan F,, Bayliss PE,, Rinn JL,, Whetstine JR,, Wang JK,, Chen S,, Iwase S,, Alpatov R,, Issaeva I,, Canaani E,, Roberts TM,, Chang HY,, Shi Y . 2007. A histone H3 lysine 27 demethylase regulates animal posterior development. Nature 449 : 689694.
53. Satoh T,, Takeuchi O,, Vandenbon A,, Yasuda K,, Tanaka Y,, Kumagai Y,, Miyake T,, Matsushita K,, Okazaki T,, Saitoh T,, Honma K,, Matsuyama T,, Yui K,, Tsujimura T,, Standley DM,, Nakanishi K,, Nakai K,, Akira S . 2010. The Jmjd3-Irf4 axis regulates M2 macrophage polarization and host responses against helminth infection. Nat Immunol 11 : 936944.
54. Takeuchi O,, Akira S . 2010. Pattern recognition receptors and inflammation. Cell 140 : 805820.
55. Seth RB,, Sun L,, Ea CK,, Chen ZJ . 2005. Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-κB and IRF 3. Cell 122 : 669682.
56. Xu LG,, Wang YY,, Han KJ,, Li LY,, Zhai Z,, Shu HB . 2005. VISA is an adapter protein required for virus-triggered IFN-β signaling. Mol Cell 19 : 727740.
57. Kawai T,, Takahashi K,, Sato S,, Coban C,, Kumar H,, Kato H,, Ishii KJ,, Takeuchi O,, Akira S . 2005. IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction. Nat Immunol 6 : 981988.
58. Satoh T,, Kidoya H,, Naito H,, Yamamoto M,, Takemura N,, Nakagawa K,, Yoshioka Y,, Morii E,, Takakura N,, Takeuchi O,, Akira S . 2013. Critical role of Trib1 in differentiation of tissue-resident M2-like macrophages. Nature 495 : 524528.
59. Biswas SK,, Mantovani A . 2010. Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat Immunol 11 : 889896.
60. Gordon S,, Plüddemann A,, Martinez Estrada F . 2014. Macrophage heterogeneity in tissues: phenotypic diversity and functions. Immunol Rev 262 : 3655.
61. Sica A,, Invernizzi P,, Mantovani A . 2014. Macrophage plasticity and polarization in liver homeostasis and pathology. Hepatology 59 : 20342042.
62. Wynn TA,, Chawla A,, Pollard JW . 2013. Macrophage biology in development, homeostasis and disease. Nature 496 : 445455.
63. Asano K,, Nabeyama A,, Miyake Y,, Qiu CH,, Kurita A,, Tomura M,, Kanagawa O,, Fujii S,, Tanaka M . 2011. CD169-positive macrophages dominate antitumor immunity by crosspresenting dead cell-associated antigens. Immunity 34 : 8595.
64. Auffray C,, Fogg D,, Garfa M,, Elain G,, Join-Lambert O,, Kayal S,, Sarnacki S,, Cumano A,, Lauvau G,, Geissmann F . 2007. Monitoring of blood vessels and tissues by a population of monocytes with patrolling behavior. Science 317 : 666670.
65. Carlin LM,, Stamatiades EG,, Auffray C,, Hanna RN,, Glover L,, Vizcay-Barrena G,, Hedrick CC,, Cook HT,, Diebold S,, Geissmann F . 2013. Nr4a1-dependent Ly6Clow monocytes monitor endothelial cells and orchestrate their disposal. Cell 153 : 362375.
66. Cheong C,, Matos I,, Choi JH,, Dandamudi DB,, Shrestha E,, Longhi MP,, Jeffrey KL,, Anthony RM,, Kluger C,, Nchinda G,, Koh H,, Rodriguez A,, Idoyaga J,, Pack M,, Velinzon K,, Park CG,, Steinman RM . 2010. Microbial stimulation fully differentiates monocytes to DC-SIGN/CD209+ dendritic cells for immune T cell areas. Cell 143 : 416429.
67. Kohyama M,, Ise W,, Edelson BT,, Wilker PR,, Hildner K,, Mejia C,, Frazier WA,, Murphy TL,, Murphy KM . 2009. Role for Spi-C in the development of red pulp macrophages and splenic iron homeostasis. Nature 457 : 318321.
68. Kumamoto Y,, Linehan M,, Weinstein JS,, Laidlaw BJ,, Craft JE,, Iwasaki A . 2013. CD301b+ dermal dendritic cells drive T helper 2 cell-mediated immunity. Immunity 39 : 733743.
69. Rosas M,, Davies LC,, Giles PJ,, Liao CT,, Kharfan B,, Stone TC,, O’Donnell VB,, Fraser DJ,, Jones SA,, Taylor PR . 2014. The transcription factor Gata6 links tissue macrophage phenotype and proliferative renewal. Science 344 : 645648.

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