Login Register Cart 0
Generic placeholder image

Current Signal Transduction Therapy

Editor-in-Chief

ISSN (Print): 1574-3624
ISSN (Online): 2212-389X

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
General Review Article

Targeting Negative Regulators of TRIF-dependent TLR Signaling Pathway as a Novel Therapeutic Strategy

Author(s): P. Mosaddeghi, N. Nezafat*, M. Negahdaripour, M. Eslami and Y. Ghasemi*

Volume 14, Issue 1, 2019

Page: [49 - 54] Pages: 6

DOI: 10.2174/1574362413666180517093038

Price: $65

Abstract

Background: Toll-Like Receptors (TLRs) are a subclass of pathogen-associated molecular patterns (PAMPs). There is a growing interest in the use of TLR agonists for various pathological dysfunctions, including cancer, microbial infections, and inflammatory diseases. TLR3/4 agonists that can induce TIR-domain-containing adapter-inducing interferon-β (TRIF)- dependent pathway have shown fewer toxic immunostimulatory responses in comparison to other small molecules. Furthermore, TLR3 agonists indicate promising anti-tumor potential in cancer immunotherapy either as vaccine adjuvant or monotherapy.

Objective: It is logical to assume that the induction of the genes that are involved in TRIF pathway to augment their pleiotropic effects on different cells via TLR agonists, could enhance the treatment process of disease while minimizing the toxicity related to using other small molecules.

Methods: An extensive literature search to identify the negative regulators of TRIF-dependent signaling pathway and their biological functions was performed from two databases PubMed and Scopus.

Results: Negative regulators of TRIF signaling pathways were identified. In addition, structure and function of sterile α- and armadillo-motif containing protein (SARM), the only TIR domaincontaining adaptor protein that inhibits TRIF-dependent activation, were briefly reviewed.

Conclusion: We proposed that the manipulation of TRIF signaling pathway via targeting its negative regulators could be used as an approach to modulate the functions of this pathway without undesired toxic proinflammatory responses.

Keywords: Toll-like receptors, sterile α- and armadillo-motif containing protein, TRIF signaling pathway, innate immunity, immunotherapy, MyD88 adaptor.

Graphical Abstract

[1]
Lemaitre B, Nicolas E, Michaut L, Reichhart JM, Hoffmann JA. The dorsoventral regulatory gene cassette spatzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 1996; 86(6): 973-83.
[2]
O’Neill LA, Golenbock D, Bowie AG. The history of toll-like receptors-redefining innate immunity. Nat Rev Immunol 2013; 13(6): 453-60.
[3]
Kaczanowska S, Joseph AM, Davila E. TLR agonists: Our best frenemy in cancer immunotherapy. J Leukoc Biol 2013; 93(6): 847-63.
[4]
Hennessy EJ, Parker AE, O’Neill LA. Targeting toll-like receptors: Emerging therapeutics? Nat Rev Drug Discov 2010; 9(4): 293-307.
[5]
Zom GG, Khan S, Filippov DV, Ossendorp F. TLR ligand-peptide conjugate vaccines: Toward clinical application. Adv Immunol 2012; 114: 177-201.
[6]
Takeda K, Akira S. TLR signaling pathways. Semin Immunol 2004; 16(1): 3-9.
[7]
Chaturvedi A, Pierce SK. How location governs toll-like receptor signaling. Traffic 2009; 10(6): 621-8.
[8]
Takeda K, Akira S. Toll-like receptors in innate immunity. Int Immunol 2005; 17(1): 1-14.
[9]
O’Neill LA, Bowie AG. The family of five: TIR-domain-containing adaptors in toll-like receptor signalling. Nat Rev Immunol 2007; 7(5): 353-64.
[10]
Hussein WM, Liu TY, Skwarczynski M, Toth I. Toll-like receptor agonists: a patent review (2011 - 2013). Exp Opin Therap Patent 2014; 24(4): 453-70.
[11]
Kolb JP, Casella CR, SenGupta S, Chilton PM, Mitchell TC. Type I interferon signaling contributes to the bias that toll-like receptor 4 exhibits for signaling mediated by the adaptor protein TRIF. Sci Signal 2014; 7(351): ra108.
[12]
Pradere JP, Dapito DH, Schwabe RF. The Yin and Yang of toll-like receptors in cancer. Oncogene 2014; 33(27): 3485-95.
[13]
Dunne A, Marshall NA, Mills KH. TLR based therapeutics. Curr Opin Pharmacol 2011; 11(4): 404-11.
[14]
Monlish DA, Bhatt ST, Schuettpelz LG. The role of toll-like receptors in hematopoietic malignancies. Front Immunol 2016; 7: 390.
[15]
Seya T, Shime H, Takeda Y, Tatematsu M, Takashima K, Matsumoto M. Adjuvant for vaccine immunotherapy of cancer focusing on toll‐like receptor 2 and 3 agonists for safely enhancing antitumor immunity. Cancer Sci 2015; 106(12): 1659-68.
[16]
Hyun J, Kanagavelu S, Fukata M. A unique host defense pathway: TRIF mediates both antiviral and antibacterial immune responses. Microbes Infect 2013; 15(1): 1-10.
[17]
Ullah MO, Sweet MJ, Mansell A, Kellie S, Kobe B. TRIF-dependent TLR signaling, its functions in host defense and inflammation, and its potential as a therapeutic target. J Leukoc Biol 2016; 100(1): 27-45.
[18]
Kim TH, Shin SJ, Park YM, et al. Critical role of TRIF and MyD88 in Mycobacterium tuberculosis Hsp70-mediated activation of dendritic cells. Cytokine 2015; 71(2): 139-44.
[19]
Borkowski AW, Kuo IH, Bernard JJ, et al. Toll-like receptor 3 activation is required for normal skin barrier repair following UV damage. J Invest Dermatol 2015; 135(2): 569-78.
[20]
Ramnath D, Powell EE, Scholz GM, Sweet MJ. The toll-like receptor 3 pathway in homeostasis, responses to injury and wound repair. Semin Cell Dev Biol 2017; 61: 22-30.
[21]
Matin N, Tabatabaie O, Mohammadinejad P, Rezaei N. Therapeutic targeting of toll-like receptors in cutaneous disorders. Expert Opin Ther Targets 2015; 19(12): 1651-63.
[22]
Kayagaki N, Phung Q, Chan S, et al. DUBA: A deubiquitinase that regulates type I interferon production. Science 2007; 318(5856): 1628-32.
[23]
Biswas N, Liu S, Ronni T, et al. The ubiquitin-like protein PLIC-1 or ubiquilin 1 inhibits TLR3-Trif signaling. PLoS One 2011; 6(6): e21153.
[24]
Xue Q, Zhou Z, Lei X, et al. TRIM38 negatively regulates TLR3-mediated IFN-beta signaling by targeting TRIF for degradation. PLoS One 2012; 7(10): e46825.
[25]
Jabir MS, Ritchie ND, Li D, et al. Caspase-1 cleavage of the TLR adaptor TRIF inhibits autophagy and beta-interferon production during Pseudomonas aeruginosa infection. Cell Host Microbe 2014; 15(2): 214-27.
[26]
Inomata M, Niida S, Shibata K, Into T. Regulation of toll-like receptor signaling by NDP52-mediated selective autophagy is normally inactivated by A20. Cell Mol Life Sci 2012; 69(6): 963-79.
[27]
Saitoh T, Tun-Kyi A, Ryo A, et al. Negative regulation of interferon-regulatory factor 3-dependent innate antiviral response by the prolyl isomerase Pin1. Nat Immunol 2006; 7(6): 598-605.
[28]
An H, Zhao W, Hou J, et al. SHP-2 phosphatase negatively regulates the TRIF adaptor protein-dependent type I interferon and proinflammatory cytokine production. Immunity 2006; 25(6): 919-28.
[29]
Yoshimura A, Naka T, Kubo M. SOCS proteins, cytokine signalling and immune regulation. Nat Rev Immunol 2007; 7(6): 454-65.
[30]
Yu Y, Hayward GS. The ubiquitin E3 ligase RAUL negatively regulates type I interferon through ubiquitination of the transcription factors IRF7 and IRF3. Immunity 2010; 33(6): 863-77.
[31]
Higgs R, Gabhann JN, Larbi NB, Breen EP, Fitzgerald KA, Jefferies CA. The E3 ubiquitin ligase RO52 negatively regulates IFN-β production post-pathogen recognition by polyubiquitin-mediated degradation of IRF3. J Immunol 2008; 181(3): 1780-6.
[32]
Zhang M, Tian Y, Wang RP, et al. Negative feedback regulation of cellular antiviral signaling by RBCK1-mediated degradation of IRF3. Cell Res 2008; 18(11): 1096-104.
[33]
Kim EJ, Lee SM, Suk K, Lee WH. CD300a and CD300f differentially regulate the MyD88 and TRIF-mediated TLR signalling pathways through activation of SHP-1 and/or SHP-2 in human monocytic cell lines. Immunology 2012; 135(3): 226-35.
[34]
Carlsson E, Ding JL, Byrne B. SARM modulates MyD88-mediated TLR activation through BB-loop dependent TIR-TIR interactions. Biochim Biophys Acta 2016; 1863(2): 244-53.
[35]
Peng J, Yuan Q, Lin B, et al. SARM inhibits both TRIF- and MyD88-mediated AP-1 activation. Eur J Immunol 2010; 40(6): 1738-47.
[36]
Panneerselvam P, Singh LP, Ho B, Chen J, Ding JL. Targeting of pro-apoptotic TLR adaptor SARM to mitochondria: Definition of the critical region and residues in the signal sequence. Biochem J 2012; 442(2): 263-71.
[37]
Kim Y, Zhou P, Qian L, et al. MyD88-5 links mitochondria, microtubules, and JNK3 in neurons and regulates neuronal survival. J Exp Med 2007; 204(9): 2063-74.
[38]
Mukherjee P, Winkler CW, Taylor KG, et al. SARM1, Not MyD88, mediates TLR7/TLR9-induced apoptosis in neurons. J Immunol 2015; 195(10): 4913-21.
[39]
Mukherjee P, Woods TA, Moore RA, Peterson KE. Activation of the innate signaling molecule MAVS by bunyavirus infection upregulates the adaptor protein SARM1, leading to neuronal death. Immunity 2013; 38(4): 705-16.
[40]
Osterloh JM, Yang J, Rooney TM, et al. dSarm/Sarm1 is required for activation of an injury-induced axon death pathway. Science 2012; 337(6093): 481-4.
[41]
Conforti L, Gilley J, Coleman MP. Wallerian degeneration: An emerging axon death pathway linking injury and disease. Nat Rev Neurosci 2014; 15(6): 394-409.
[42]
Ve T, Williams SJ, Kobe B. Structure and function of Toll/interleukin-1 receptor/resistance protein (TIR) domains. Apoptosis 2015; 20(2): 250-61.
[43]
Murgueitio MS, Rakers C, Frank A, Wolber G. Balancing inflammation: Computational design of small-molecule toll-like receptor modulators. Trends Pharmacol Sci 2017; 38(2): 155-68.
[44]
Olson MA, Lee MS, Kissner TL, Alam S, Waugh DS, Saikh KU. Discovery of small molecule inhibitors of MyD88-dependent signaling pathways using a computational screen. Sci Rep 2015; 5: 14246.
[45]
Mistry P, Laird MH, Schwarz RS, et al. Inhibition of TLR2 signaling by small molecule inhibitors targeting a pocket within the TLR2 TIR domain. Proc Natl Acad Sci USA 2015; 112(17): 5455-60.
[46]
Summers DW, Gibson DA, DiAntonio A, Milbrandt J. SARM1-specific motifs in the TIR domain enable NAD+ loss and regulate injury-induced SARM1 activation. Proc Natl Acad Sci USA 2016; 113(41): E6271-e80.
[47]
Lu H. TLR agonists for cancer immunotherapy: Tipping the balance between the immune stimulatory and inhibitory effects. Front Immunol 2014; •••: 5.
[48]
Akazawa T, Ebihara T, Okuno M, et al. Antitumor NK activation induced by the toll-like receptor 3-TICAM-1 (TRIF) pathway in myeloid dendritic cells. Proc Natl Acad Sci USA 2007; 104(1): 252-7.
[49]
Shime H, Matsumoto M, Oshiumi H, et al. Toll-like receptor 3 signaling converts tumor-supporting myeloid cells to tumoricidal effectors. Proc Natl Acad Sci USA 2012; 109(6): 2066-71.
[50]
Matsumoto M, Tatematsu M, Nishikawa F, et al. Defined TLR3-specific adjuvant that induces NK and CTL activation without significant cytokine production in vivo. Nat Commun 2015; 6: 6280.
[51]
Mata-Haro V, Cekic C, Martin M, Chilton PM, Casella CR, Mitchell TC. The vaccine adjuvant monophosphoryl lipid A as a TRIF-biased agonist of TLR4. Science 2007; 316(5831): 1628-32.
[52]
Baral P, Utaisincharoen P. Sterile-α- and armadillo motif-containing protein inhibits the TRIF-dependent downregulation of signal regulatory protein α to interfere with intracellular bacterial elimination in burkholderia pseudomallei-infected mouse macrophages. Infect Immun 2013; 81(9): 3463-71.
[53]
Honda K, Yanai H, Negishi H, et al. IRF-7 is the master regulator of type-I interferon-dependent immune responses. Nature 2005; 434(7034): 772-7.
[54]
Panneerselvam P, Singh LP, Selvarajan V, et al. T-cell death following immune activation is mediated by mitochondria-localized SARM. Cell Death Differ 2013; 20(3): 478-89.
[55]
Fukata M, Arditi M. The role of pattern recognition receptors in intestinal inflammation. Mucosal Immunol 2013; 6(3): 451-63.
[56]
Cole JE, Navin TJ, Cross AJ, et al. Unexpected protective role for toll-like receptor 3 in the arterial wall. Proc Natl Acad Sci USA 2011; 108(6): 2372-7.
[57]
Richards MR, Black AS, Bonnet DJ, et al. The LPS2 mutation in TRIF is atheroprotective in hyperlipidemic LDL receptor knockout mice. Innate Immun 2013; 19(1): 20-9.
[58]
Rahman FZ, Smith AM, Hayee B, Marks DJ, Bloom SL, Segal AW. Delayed resolution of acute inflammation in ulcerative colitis is associated with elevated cytokine release downstream of TLR4. PLoS One 2010; 5(3): e9891.
[59]
Lundberg AM, Ketelhuth DF, Johansson ME, et al. Toll-like receptor 3 and 4 signalling through the TRIF and TRAM adaptors in haematopoietic cells promotes atherosclerosis. Cardiovasc Res 2013; 99(2): 364-73.
[60]
Yarilina A, DiCarlo E, Ivashkiv LB. Suppression of the effector phase of inflammatory arthritis by double-stranded RNA is mediated by type I IFNs. J Immunol 2007; 178(4): 2204-11.
[61]
Abdollahi-Roodsaz S, van de Loo FA, Koenders MI, et al. Destructive role of myeloid differentiation factor 88 and protective role of TRIF in interleukin-17-dependent arthritis in mice. Arthritis Rheum 2012; 64(6): 1838-47.
[62]
Portou MJ, Baker D, Abraham D, Tsui J. The innate immune system, toll-like receptors and dermal wound healing: A review. Vascul Pharmacol 2015; 71: 31-6.
[63]
Lin Q, Wang L, Lin Y, et al. Toll-like receptor 3 ligand polyinosinic:polycytidylic acid promotes wound healing in human and murine skin. J Invest Dermatol 2012; 132(8): 2085-92.
[64]
Adams JL, Smothers J, Srinivasan R, Hoos A. Big opportunities for small molecules in immuno-oncology. Nat Rev Drug Discov 2015; 14(9): 603-22.
[65]
Rakoff-Nahoum S, Medzhitov R. Toll-like receptors and cancer. Nat Rev Cancer 2009; 9(1): 57-63.
[66]
Liu B, Liu Q, Yang L, et al. Innate immune memory and homeostasis may be conferred through crosstalk between the TLR3 and TLR7 pathways. Sci Signal 2016; 9(436): ra70.
[67]
Mahmoodi S, Nezafat N, Barzegar A, et al. Harnessing bioinformatics for designing a novel multiepitope peptide vaccine against breast cancer. Curr Pharm Biotechnol 2016; 17(12): 1100-14.
[68]
Nezafat N, Eslami M, Negahdaripour M, Rahbar MR, Ghasemi Y. Designing an efficient multi-epitope oral vaccine against Helicobacter pylori using immunoinformatics and structural vaccinology approaches. Mol Biosyst 2017; 13(4): 699-713.
[69]
Hajighahramani N, Nezafat N, Eslami M, Negahdaripour M, Rahmatabadi SS, Ghasemi Y. Immunoinformatics analysis and in silico designing of a novel multi-epitope peptide vaccine against Staphylococcus aureus. Infect Genet Evol J Mol Epidemiol Evol Genet Infect Dis 2017; 48: 83-94.
[70]
Nezafat N, Karimi Z, Eslami M, Mohkam M, Zandian S, Ghasemi Y. Designing an efficient multi-epitope peptide vaccine against Vibrio cholerae via combined immunoinformatics and protein interaction based approaches. Comput Biol Chem 2016; 62: 82-95.
[71]
Nezafat N, Ghasemi Y, Javadi G, Khoshnoud MJ, Omidinia E. A novel multi-epitope peptide vaccine against cancer: an in silico approach. J Theor Biol 2014; 349: 121-34.
[72]
Vandenbon A, Teraguchi S, Akira S, Takeda K, Standley DM. Systems biology approaches to toll-like receptor signaling. Wiley Tnterdisciplin Rev Syst Biol Med 2012; 4(5): 497-507.
[73]
Shannon P, Markiel A, Ozier O, et al. Cytoscape: A software environment for integrated models of biomolecular interaction networks. Genome Res 2003; 13(11): 2498-504.

Rights & Permissions Print Cite
Article Metrics
80
2
© 2024 Bentham Science Publishers | Privacy Policy