J Bacteriol Virol.  2014 Sep;44(3):215-225. 10.4167/jbv.2014.44.3.215.

Toll-like Receptors and NOD-like Receptors in Innate Immune Defense during Pathogenic Infection

Affiliations
  • 1Department of Microbiology, Chungnam National University School of Medicine, Daejeon, Korea. hayoungj@cnu.ac.kr
  • 2Infection Signaling Network Research Center, Chungnam National University School of Medicine, Daejeon, Korea.

Abstract

In response to invading pathogens, the body immune system develops an immediate defense mechanism, i.e., innate immune response, which is detected in almost all living organisms including mammals, plants, insects, etc. Recent studies have identified numerous innate immune receptors that are able to recognize pathogen-associated molecular patterns and transduce the essential intracellular signaling cascades to mount early and successful host defenses against infectious challenge. Among innate immune receptors, we will focus on two important receptors, toll-like receptors (TLRs) and nucleotide binding oligomerization domain (Nod)-like receptors, and their major intracellular signaling pathways that culminate to activate innate immune effectors and inflammatory mediators during pathogen infection. In this review, we address the recent advances of understanding intracellular signaling mechanisms by which TLRs and NLRs activate host immune defense and inflammation. The role and regulatory mechanisms by which a subet of NLRs-associated inflammasome activation induce interleukin-1beta secretion and their relevance with host defense will be also discussed. Both TLR- and NLR-mediated intracellular signaling networks serve crucial roles in mounting resistance to bacterial and viral infection through synthesis of immune mediators and antimicrobial chemicals during infection.

Keyword

Toll-like receptors; Nod-like receptors; Inflammasome; Host defense; Infection; Innate immunity

MeSH Terms

Immune System
Immunity, Innate
Inflammation
Insects
Interleukin-1beta
Mammals
Toll-Like Receptors*
Interleukin-1beta
Toll-Like Receptors

Figure

  • Figure 1. Schematic diagrams of innate immune receptors. (Left) Toll-like receptor (TLR) signaling is activated by TLR ligands. TLRs which located in plasma membrane (TLR1, 2, 4, 5, 6, 11) activate NF-κB and MAPK (JNK, ERK, p38) signaling pathway via MyD88. Nucleic acid recognition by endosomal TLRs (TLR3, 7, 8, 9) induces production of type I interferon and proinflammatory cytokines via TRIF-IRF3 and MyD88-NF-κB signaling pathways, respectively. (Middle) NOD1 and NOD2 recognize γ-D-glutamyl-meso-diaminopimelic acid (meso-DAP) and muramic dipeptide (MDP) from bacterial cell wall components, respectively. NOD-induced proinflammatory responses require MAPK and NF-κB activation through the recruitment of adaptor molecule CARD9 and RICK. (Right) Certain members of NOD-like receptors (NLRs) participate in the activation of inflammasome complex consisting of NLRs, procaspase-1 and ASC in the cytosol. Multiple ligands or stimulators including various pathogen-associated molecular patterns, damage-associated molecular patterns, and microbes, have been identified to activate inflammasome complex to produce mature IL-1β and IL-18 through activation of caspase-1.


Cited by  1 articles

Heat Shock Protein 90 (HSP90) and Immune Regulation
Bo-Kyung Kim, So-Youn Woo
J Bacteriol Virol. 2015;45(1):62-66.    doi: 10.4167/jbv.2015.45.1.62.


Reference

1). Delneste Y, Beauvillain C, Jeannin P. Innate immunity: structure and function of TLRs. Med Sci (Paris). 2007; 23:67–73.
2). Jeong E, Lee JY. Intrinsic and extrinsic regulation of innate immune receptors. Yonsei Med J. 2011; 52:379–92.
Article
3). Kawai T, Akira S. Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity. 2011; 34:637–50.
Article
4). Kawai T, Akira S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol. 2010; 11:373–84.
Article
5). Kumar S, Ingle H, Prasad DV, Kumar H. Recognition of bacterial infection by innate immune sensors. Crit Rev Microbiol. 2013; 39:229–46.
Article
6). Kawai T, Akira S. Signaling to NF-kappaB by Toll-like receptors. Trends Mol Med. 2007; 13:460–9.
7). Kanneganti TD, Lamkanfi M, Núñez G. Intracellular NOD-like receptors in host defense and disease. Immunity. 2007; 27:549–59.
Article
8). Franchi L, Park JH, Shaw MH, Marina-Garcia N, Chen G, Kim YG, et al. Intracellular NOD-like receptors in innate immunity, infection and disease. Cell Microbiol. 2008; 10:1–8.
Article
9). Rietdijk ST, Burwell T, Bertin J, Coyle AJ. Sensing intracellular pathogens-NOD-like receptors. Curr Opin Pharmacol. 2008; 8:261–6.
Article
10). Philpott DJ, Girardin SE. Nod-like receptors: sentinels at host membranes. Curr Opin Immunol. 2010; 22:428–34.
Article
11). Lee CC, Avalos AM, Ploegh HL. Accessory molecules for Toll-like receptors and their function. Nat Rev Immunol. 2012; 12:168–79.
Article
12). Kawai T, Akira S. TLR signaling. Cell Death Differ. 2006; 13:816–25.
Article
13). Takaesu G, Ninomiya-Tsuji J, Kishida S, Li X, Stark GR, Matsumoto K. Interleukin-1 (IL-1) receptor-associated kinase leads to activation of TAK1 by inducing TAB2 translocation in the IL-1 signaling pathway. Mol Cell Biol. 2001; 21:2475–84.
Article
14). Landström M. The TAK1-TRAF6 signalling pathway. Int J Biochem Cell Biol. 2010; 42:585–9.
Article
15). Brown J, Wang H, Hajishengallis GN, Martin M. TLR-signaling networks: an integration of adaptor molecules, kinases, and cross-talk. J Dent Res. 2011; 90:417–27.
16). Tseng PH, Matsuzawa A, Zhang W, Mino T, Vignali DA, Karin M. Different modes of ubiquitination of the adaptor TRAF3 selectively activate the expression of type I interferons and proinflammatory cytokines. Nat Immunol. 2010; 11:70–5.
Article
17). Horng T, Barton GM, Medzhitov R. TIRAP: an adapter molecule in the Toll signaling pathway. Nat Immunol. 2001; 2:835–41.
Article
18). Yamamoto M, Takeda K, Akira S. TIR domain-containing adaptors define the specificity of TLR signaling. Mol Immunol. 2004; 40:861–8.
Article
19). Shaw PJ, Lamkanfi M, Kanneganti TD. NOD-like receptor (NLR) signaling beyond the inflammasome. Eur J Immunol. 2010; 40:624–7.
Article
20). Shaw MH, Reimer T, Kim YG, Nuñez G. NOD-like receptors (NLRs): bona fide intracellular microbial sensors. Curr Opin Immunol. 2008; 20:377–82.
Article
21). Chamaillard M, Hashimoto M, Horie Y, Masumoto J, Qiu S, Saab L, et al. An essential role for NOD1 in host recognition of bacterial peptidoglycan containing diaminopimelic acid. Nat Immunol. 2003; 4:702–7.
Article
22). Girardin SE, Boneca IG, Carneiro LA, Antignac A, Jéhanno M, Viala J, et al. Nod1 detects a unique muropeptide from gram-negative bacterial peptidoglycan. Science. 2003; 300:1584–7.
Article
23). Girardin SE, Boneca IG, Viala J, Chamaillard M, Labigne A, Thomas G, et al. Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection. J Biol Chem. 2003; 278:8869–72.
Article
24). Inohara N, Ogura Y, Fontalba A, Gutierrez O, Pons F, Crespo J, et al. Host recognition of bacterial muramyl dipeptide mediated through NOD2. Implications for Crohn's disease. J Biol Chem. 2003; 278:5509–12.
25). Inohara , Chamaillard , McDonald C, Nuñez G. NOD-LRR proteins: role in host-microbial interactions and inflammatory disease. Annu Rev Biochem. 2005; 74:355–83.
Article
26). Inohara N, Koseki T, Lin J, del Peso L, Lucas PC, Chen FF, et al. An induced proximity model for NF-kappa B activation in the Nod1/RICK and RIP signaling pathways. J Biol Chem. 2000; 275:27823–31.
27). Girardin SE, Tournebize R, Mavris M, Page AL, Li X, Stark GR, et al. CARD4/Nod1 mediates NF-kappaB and JNK activation by invasive Shigella flexneri. EMBO Rep. 2001; 2:736–42.
28). Park JH, Kim YG, McDonald C, Kanneganti TD, Hasegawa M, Body-Malapel M, et al. RICK/RIP2 mediates innate immune responses induced through Nod1 and Nod2 but not TLRs. J Immunol. 2007; 178:2380–6.
Article
29). Park JH, Kim YG, Shaw M, Kanneganti TD, Fujimoto Y, Fukase K, et al. Nod1/RICK and TLR signaling regulate chemokine and antimicrobial innate immune responses in mesothelial cells. J Immunol. 2007; 179:514–21.
Article
30). Hasegawa M, Fujimoto Y, Lucas PC, Nakano H, Fukase K, Núñez G, et al. A critical role of RICK/RIP2 polyubiquitination in Nod-induced NF-kappaB activation. EMBO J. 2008; 27:373–83.
31). Tigno-Aranjuez JT, Abbott DW. Ubiquitination and phosphorylation in the regulation of NOD2 signaling and NOD2-mediated disease. Biochim Biophys Acta. 2012; 1823:2022–8.
Article
32). Krieg A, Correa RG, Garrison JB, Le Negrate G, Welsh K, Huang Z, et al. XIAP mediates NOD signaling via interaction with RIP2. Proc Natl Acad Sci U S A. 2009; 106:14524–9.
Article
33). Tattoli I, Travassos LH, Carneiro LA, Magalhaes JG, Girardin SE. The Nodosome: Nod1 and Nod2 control bacterial infections and inflammation. Semin Immunopathol. 2007; 29:289–301.
Article
34). da Silva Correia J, Miranda Y, Leonard N, Hsu J, Ulevitch RJ. Regulation of Nod1-mediated signaling pathways. Cell Death Differ. 2007; 14:830–9.
Article
35). Windheim M, Lang C, Peggie M, Plater LA, Cohen P. Molecular mechanisms involved in the regulation of cytokine production by muramyl dipeptide. Biochem J. 2007; 404:179–90.
Article
36). Kim JY, Omori E, Matsumoto K, Núñez G, Ninomiya-Tsuji J. TAK1 is a central mediator of NOD2 signaling in epidermal cells. J Biol Chem. 2008; 283:137–44.
Article
37). Hsu YM, Zhang Y, You Y, Wang D, Li H, Duramad O, et al. The adaptor protein CARD9 is required for innate immune responses to intracellular pathogens. Nat Immunol. 2007; 8:198–205.
Article
38). Hedl M, Abraham C. Distinct roles for Nod2 protein and autocrine interleukin-1beta in muramyl dipeptide-induced mitogen-activated protein kinase activation and cytokine secretion in human macrophages. J Biol Chem. 2011; 286:26440–9.
39). Rathinam VA, Vanaja SK, Fitzgerald KA. Regulation of inflammasome signaling. Nat Immunol. 2012; 13:333–42.
Article
40). Vladimer GI, Marty-Roix R, Ghosh S, Weng D, Lien E. Inflammasomes and host defenses against bacterial infections. Curr Opin Microbiol. 2013; 16:23–31.
Article
41). Lukens JR, Dixit VD, Kanneganti TD. Inflammasome activation in obesity-related inflammatory diseases and autoimmunity. Discov Med. 2011; 12:65–74.
42). Shaw PJ, McDermott MF, Kanneganti TD. Inflammasomes and autoimmunity. Trends Mol Med. 2011; 17:57–64.
Article
43). Franchi L, Amer A, Body-Malapel M, Kanneganti TD, Ozören N, Jagirdar R, et al. Cytosolic flagellin requires Ipaf for activation of caspase-1 and interleukin 1beta in salmonella-infected macrophages. Nat Immunol. 2006; 7:576–82.
44). Miao EA, Alpuche-Aranda CM, Dors M, Clark AE, Bader MW, Miller SI, et al. Cytoplasmic flagellin activates caspase-1 and secretion of interleukin 1beta via Ipaf. Nat Immunol. 2006; 7:569–75.
45). Miao EA, Mao DP, Yudkovsky N, Bonneau R, Lorang CG, Warren SE, et al. Innate immune detection of the type III secretion apparatus through the NLRC4 inflammasome. Proc Natl Acad Sci U S A. 2010; 107:3076–80.
Article
46). Miao EA, Andersen-Nissen E, Warren SE, Aderem A. TLR5 and Ipaf: dual sensors of bacterial flagellin in the innate immune system. Semin Immunopathol. 2007; 29:275–88.
Article
47). Zhao Y, Yang J, Shi J, Gong YN, Lu Q, Xu H, et al. The NLRC4 inflammasome receptors for bacterial flagellin and type III secretion apparatus. Nature. 2011; 477:596–600.
Article
48). Kofoed EM, Vance RE. Innate immune recognition of bacterial ligands by NAIPs determines inflammasome specificity. Nature. 2011; 477:592–5.
Article
49). Zamboni DS, Kobayashi KS, Kohlsdorf T, Ogura Y, Long EM, Vance RE, et al. The Birc1e cytosolic pattern-recognition receptor contributes to the detection and control of Legionella pneumophila infection. Nat Immunol. 2006; 7:318–25.
50). Ren T, Zamboni DS, Roy CR, Dietrich WF, Vance RE. Flagellin-deficient Legionella mutants evade caspase-1- and Naip5-mediated macrophage immunity. PLoS Pathog. 2006; 2:e18.
51). Miao EA, Ernst RK, Dors M, Mao DP, Aderem A. Pseudomonas aeruginosa activates caspase 1 through Ipaf. Proc Natl Acad Sci U S A. 2008; 105:2562–7.
52). Franchi L, Stoolman J, Kanneganti TD, Verma A, Ramphal R, Núñez G. Critical role for Ipaf in Pseudomonas aeruginosa-induced caspase-1 activation. Eur J Immunol. 2007; 37:3030–9.
53). Aachoui Y, Sagulenko V, Miao EA, Stacey KJ. Inflammasome-mediated pyroptotic and apoptotic cell death, and defense against infection. Curr Opin Microbiol. 2013; 16:319–26.
Article
54). Franchi L, Muñoz-Planillo R, Núñez G. Sensing and reacting to microbes through the inflammasomes. Nat Immunol. 2012; 13:325–32.
Article
55). Broz P, Monack DM. Molecular mechanisms of inflammasome activation during microbial infections. Immunol Rev. 2011; 243:174–90.
Article
56). von Moltke J, Trinidad NJ, Moayeri M, Kintzer AF, Wang SB, van Rooijen N, et al. Rapid induction of inflammatory lipid mediators by the inflammasome in vivo. Nature. 2012; 490:107–11.
57). Qu Y, Misaghi S, Izrael-Tomasevic A, Newton K, Gilmour LL, Lamkanfi M, et al. Phosphorylation of NLRC4 is critical for inflammasome activation. Nature. 2012; 490:539–42.
Article
58). Leemans JC, Cassel SL, Sutterwala FS. Sensing damage by the NLRP3 inflammasome. Immunol Rev. 2011; 243:152–62.
Article
59). Muñoz-Planillo R, Franchi L, Miller LS, Núñez G. A critical role for hemolysins and bacterial lipoproteins in Staphylococcus aureus-induced activation of the Nlrp3 inflammasome. J Immunol. 2009; 183:3942–8.
60). Meixenberger K1, Pache F, Eitel J, Schmeck B, Hippenstiel S, Slevogt H, et al. Listeria monocytogenes-infected human peripheral blood mononuclear cells produce IL-1beta, depending on listeriolysin O and NLRP3. J Immunol. 2010; 184:922–30.
61). Kim S, Bauernfeind F, Ablasser A, Hartmann G, Fitzgerald KA, Latz E, et al. Listeria monocytogenes is sensed by the NLRP3 and AIM2 inflammasome. Eur J Immunol. 2010; 40:1545–51.
62). Willingham SB, Allen IC, Bergstralh DT, Brickey WJ, Huang MT, Taxman DJ, et al. NLRP3 (NALP3, Cryopyrin) facilitates in vivo caspase-1 activation, necrosis, and HMGB1 release via inflammasome-dependent and -independent pathways. J Immunol. 2009; 183:2008–15.
63). Duncan JA, Gao X, Huang MT, O'Connor BP, Thomas CE, Willingham SB, et al. Neisseria gonorrhoeae activates the proteinase cathepsin B to mediate the signaling activities of the NLRP3 and ASC-containing inflammasome. J Immunol. 2009; 182:6460–9.
64). Gross O, Poeck H, Bscheider M, Dostert C, Hannesschläger N, Endres S, et al. Syk kinase signalling couples to the Nlrp3 inflammasome for anti-fungal host defence. Nature. 2009; 459:433–6.
Article
65). Hise AG, Tomalka J, Ganesan S, Patel K, Hall BA, Brown GD, et al. An essential role for the NLRP3 inflammasome in host defense against the human fungal pathogen Candida albicans. Cell Host Microbe. 2009; 5:487–97.
66). Lee HM, Yuk JM, Kim KH, Jang J, Kang G, Park JB, et al. Mycobacterium abscessus activates the NLRP3 inflammasome via Dectin-1-Syk and p62/SQSTM1. Immunol Cell Biol. 2012; 90:601–10.
67). Qin M, Pirouz A, Kim MH, Krutzik SR, Garbán HJ, Kim J. Propionibacterium acnes Induces IL-1β secretion via the NLRP3 inflammasome in human monocytes. J Invest Dermatol. 2014; 134:381–8.
68). Allen IC, Scull MA, Moore CB, Holl EK, McElvania-TeKippe E, Taxman DJ, et al. The NLRP3 inflammasome mediates in vivo innate immunity to influenza A virus through recognition of viral RNA. Immunity. 2009; 30:556–65.
69). Thomas PG, Dash P, Aldridge JR Jr, Ellebedy AH, Reynolds C, Funk AJ, et al. The intracellular sensor NLRP3 mediates key innate and healing responses to influenza A virus via the regulation of caspase-1. Immunity. 2009; 30:566–75.
Article
70). Tschopp J, Schroder K. NLRP3 inflammasome activation: The convergence of multiple signalling pathways on ROS production? Nat Rev Immunol. 2010; 10:210–5.
Article
71). Davis BKWH, Ting JP. The Inflammasome NLRs in Immunity, Inflammation, and Associated Diseases. Annu Rev Immunol. 2010. :Epub.
Article
72). Bauernfeind FG, Horvath G, Stutz A, Alnemri ES, MacDonald K, Speert D, et al. Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J Immunol. 2009; 183:787–91.
73). Harder J, Franchi L, Muñoz-Planillo R, Park JH, Reimer T, Núñez G. Activation of the Nlrp3 inflammasome by Streptococcus pyogenes requires streptolysin O and NF-kappa B activation but proceeds independently of TLR signaling and P2X7 receptor. J Immunol. 2009; 183:5823–9.
74). Franchi L, Eigenbrod T, Muñoz-Planillo R, Nuñez G. The inflammasome: a caspase-1-activation platform that regulates immune responses and disease pathogenesis. Nat Immunol. 2009; 10:241–7.
Article
75). Franchi L, Eigenbrod T, Núñez G. Cutting edge: TNF-alpha mediates sensitization to ATP and silica via the NLRP3 inflammasome in the absence of microbial stimulation. J Immunol. 2009; 183:792–6.
76). Kayagaki N, Warming S, Lamkanfi M, Vande Walle L, Louie S, Dong J, et al. Non-canonical inflammasome activation targets caspase-11. Nature. 2011; 479:117–21.
Article
77). Rathinam VA, Vanaja SK, Waggoner L, Sokolovska A, Becker C, Stuart LM, et al. TRIF licenses caspase-11-dependent NLRP3 inflammasome activation by gramnegative bacteria. Cell. 2012; 150:606–19.
Article
78). Martinon F, Burns K, Tschopp J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell. 2002; 10:417–26.
79). Boyden ED, Dietrich WF. Nalp1b controls mouse macrophage susceptibility to anthrax lethal toxin. Nat Genet. 2006; 38:240–4.
Article
80). Newman ZL, Printz MP, Liu S, Crown D, Breen L, Miller-Randolph S, et al. Susceptibility to anthrax lethal toxin-induced rat death is controlled by a single chromosome 10 locus that includes rNlrp1. PLoS Pathog. 2010; 6:e1000906.
Article
81). Levinsohn JL, Newman ZL, Hellmich KA, Fattah R, Getz MA, Liu S, et al. Anthrax lethal factor cleavage of Nlrp1 is required for activation of the inflammasome. PLoS Pathog. 2012; 8:e1002638.
Article
82). Cirelli KM, Gorfu G, Hassan MA, Printz M, Crown D, Leppla SH, et al. Inflammasome sensor NLRP1 controls rat macrophage susceptibility to Toxoplasma gondii. PLoS Pathog. 2014; 10:e1003927.
83). Fernandes-Alnemri T, Yu JW, Datta P, Wu J, Alnemri ES. AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA. Nature. 2009; 458:509–13.
Article
84). Hornung V, Ablasser A, Charrel-Dennis M, Bauernfeind F, Horvath G, Caffrey DR, et al. AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC. Nature. 2009; 458:514–8.
Article
85). Fernandes-Alnemri T, Yu JW, Juliana C, Solorzano L, Kang S, Wu J, et al. The AIM2 inflammasome is critical for innate immunity to Francisella tularensis. Nat Immunol. 2010; 11:385–93.
86). Rathinam VA, Jiang Z, Waggoner SN, Sharma S, Cole LE, Waggoner L, et al. The AIM2 inflammasome is essential for host defense against cytosolic bacteria and DNA viruses. Nat Immunol. 2010; 11:395–402.
Article
87). Fang R, Hara H, Sakai S, Hernandez-Cuellar E, Mitsuyama M, Kawamura I, et al. Type I interferon signaling regulates activation of the absent in melanoma 2 inflammasome during Streptococcus pneumoniae infection. Infect Immun. 2014; 82:2310–7.
88). Park E, Na HS, Song YR, Shin SY, Kim YM, Chung J. Activation of NLRP3 and AIM2 inflammasomes by Porphyromonas gingivalis infection. Infect Immun. 2014; 82:112–23.
89). Shah S, Bohsali A, Ahlbrand SE, Srinivasan L, Rathinam VA, Vogel SN, et al. Cutting edge: Mycobacterium tuberculosis but not nonvirulent mycobacteria inhibits IFN-β and AIM2 inflammasome-dependent IL-1β production via its ESX-1 secretion system. J Immunol. 2013; 191:3514–8.
90). Wu YH, Kuo WC, Wu YJ, Yang KT, Chen ST, Jiang ST, et al. Participation of c-FLIP in NLRP3 and AIM2 inflammasome activation. Cell Death Differ. 2014; 21:451–61.
Article
91). Sagulenko V, Thygesen SJ, Sester DP, Idris A, Cridland JA, Vajjhala PR, et al. AIM2 and NLRP3 inflammasomes activate both apoptotic and pyroptotic death pathways via ASC. Cell Death Differ. 2013; 20:1149–60.
Article
Full Text Links
  • JBV
Actions
Cited
CITED
export Copy
Close
Share
  • Twitter
  • Facebook
Similar articles
Copyright © 2024 by Korean Association of Medical Journal Editors. All rights reserved.     E-mail: koreamed@kamje.or.kr