Toll-Like Receptors Signaling and Research Progress of Its Role in Organ Transplantation_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

HANG Li , HU Mingdao , CHEN Peng

Department of Hepatobiliary-Pancreatic Surgery， The Second Affiliated Hospital of Kunming Medical University， Kunming 650101， Yunnan Province， China;

Corresponding author：

Keywords：

Toll-like receptor; Organ transplantation; Ischemic reperfusion injury; Immune rejection

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Objective 　To review the research progress of Toll-like receptors （TLRs） signaling and its effects in organ transplantation.
Methods 　The structural and functional features of TLRs and their ligands were summarized，the literatures in recent years about the research progress of TLRs signaling in animal experiment and clinical organ transplantation were reviewed.
Results 　TRLs played an important role in the organ transplantation，the activation of TLRs could activate the specific immune system，and contribute to ischemic reperfusion injury，acute and chronic allograft rejections，and induce the immune tolerance. Early treatment intervention could reduce the activation of TRLs through ischemic reperfusion injury in the organ transplantation，and improve the allograft survival. The efficient immunosuppressive drugs which aimed at the related immunosuppressive target in immune and its signal transduction pathway could reduce ischemic reperfusion injury in the organ transplantation and immune rejection.
Conclusions 　TRLs signaling plays an important role in ischemic reperfusion injury，immune rejection，and immune regulation.

Citation： HANG Li,HU Mingdao,CHEN Peng,.. Toll-Like Receptors Signaling and Research Progress of Its Role in Organ Transplantation. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2012, 19(11): 1243-1248. doi: Copy

1.	Medzhitov R， Preston-Hurlburt P， Janeway CA Jr. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity[J]. Nature， 1997， 388(6640)：394-397.
2.	Takeda K， Kaisho T， Akira S. Toll-like receptors[J]. Annu Rev Immunol， 2003， 21：335-376.
3.	Asprodites N， Zheng L， Geng D， et al. Engagement of toll-like receptor-2 on cytotoxic t-lymphocytes occurs in vivo and augments antitumor activity[J]. FASEB J， 2008， 22(10)：3628-3637.
4.	Lorenz E. TLR2 and TLR4 expression during bacterial infections[J]. Curr Pharm Des， 2006， 12(32)：4185-4193.
5.	Boehme KW， Guerrero M， Compton T. Human cytomegalovirus envelope glycoproteins B and H are necessary for TLR2 activation in permissive cells[J]. J Immunol， 2006， 177(10)：7094-7102.
6.	Krasowska-Zoladek A， Banaszewska M， Kraszpulski M， et al. Kinetics of inflammatory response of astrocytes induced by TLR3 and TLR4 ligation[J]. J Neurosci Res， 2007， 85(1)：205-212.
7.	Tabeta K， Georgel P， Janssen E， et al. Toll-like receptors 9 and 3 as essential components of innate immune defense against mouse cytomegalovirus infection[J]. Proc Natl Acad Sci USA， 2004， 101(10)：3516-3521.
8.	Arbour NC， Lorenz E， Schutte BC， et al. TLR4 mutations are associated with endotoxin hyporesponsiveness in humans[J]. Nat Genet， 2000， 25(2)：187-191.
9.	Miyamoto Y， Iimura M， Kaper JB， et al. Role of Shiga toxin versus H7 flagellin in enterohaemorrhagic escherichia coli signa-ling of human colon epithelium in vivo[J]. Cell Microbiol， 2006， 8(5)：869-879.
10.	Guan Y， Ranoa DR， Jiang S， et al. Human TLRs 10 and 1 share common mechanisms of innate immune sensing but not signaling[J]. J Immunol， 2010， 184(9)：5094-5103.
11.	Lauw FN， Caffrey DR， Golenbock DT. Of mice and man：TLR11 (finally) finds profilin[J]. Trends Immunol， 2005， 26(10)：509-511.
12.	Rubartelli A， Lotze MT. Inside， outside， upside down：damage-associated molecular-pattern molecules (DAMPs) and redox[J]. Trends Immunol， 2007， 28(10)：429-436.
13.	Shirali AC， Goldstein DR. Activation of the innate immune system by the endogenous ligand hyaluronan[J]. Curr Opin Organ Transplant， 2008， 13(1)：20-25.
14.	Tesar BM， Jiang D， Liang J， et al. The role of hyaluronan degradation products as innate alloimmune agonists[J]. Am J Transplant， 2006， 6(11)：2622-2635.
15.	Pockley AG. Heat shock proteins， anti-heat shock protein reactivity and allograft rejection[J]. Transplantation， 2001， 71(11)：1503-1507.
16.	Alegre ML， Goldstein DR， Chong AS. Toll-like receptor signaling in transplantation[J]. Curr Opin Organ Transplant， 2008， 13(4)：358-365.
17.	Zhai Y， Qiao B， Shen XD， et al. Evidence for the pivotal role of endogenous toll-like receptor 4 ligands in liver ischemia and reperfusion injury[J]. Transplantation， 2008， 85(7)：1016-1022.
18.	-dependent transplant rejection[J]. J Immunol， 2009， 182 (10)：6217-6225.
19.	Beg AA. Endogenous ligands of Toll-like receptors：implications for regulating inflammatory and immune responses[J]. Trends Immunol， 2002， 23(11)：509-512.
20.	O’Neill LA， Bowie AG. The family of five：TIR-domain-containing adaptors in Toll-like receptor signalling[J]. Nat Rev Immunol， 2007， 7(5)：353-364.
21.	Choi YJ， Im E， Chung HK， et al. TRIF mediates Toll-likereceptor 5-induced signaling in intestinal epithelial cells[J]. J Biol Chem， 2010， 285(48)：37570-37578.
22.	Choi YJ， Im E， Pothoulakis C， et al. TRIF modulates TLR5-dependent responses by inducing proteolytic degradation of TLR5[J]. J Biol Chem， 2010， 285(28)：21382-21390.
23.	Liberati NT， Fitzgerald KA， Kim DH， et al. Requirement for a conserved Toll/interleukin-1 resistance domain protein in the Caenorhabditis elegans immune response[J]. Proc Natl Acad Sci USA， 2004， 101(17)：6593-6598.
24.	Wald D， Qin J， Zhao Z， et al. SIGIRR， a negative regulator of Toll-like receptor-interleukin 1 receptor signaling[J]. Nat Immunol， 2003， 4(9)：920-927.
25.	朱旭辉，杨明金. CMRF35样分子对Toll样受体信号通路的影响及其机制的研究进展[J]. 中国肿瘤生物治疗杂志， 2011， 18(1)：101-104.
26.	Goldstein DR， Tesar BM， Akira S， et al. Critical role of the Toll-like receptor signal adaptor protein MyD88 in acute allograft rejection[J]. J Clin Invest， 2003， 111(10)：1571-1578.
27.	Tesar BM， Zhang J， Li Q， et al. TH1 immune responses to fully MHC mismatched allografts are diminished in the absence of MyD88， a toll-like receptor signal adaptor protein[J]. Am J Transplant， 2004， 4(9)：1429-1439.
28.	McKay D， Shigeoka A， Rubinstein M， et al. Simultaneous deletion of MyD88 and Trif delays major histocompatibility and minor antigen mismatch allograft rejection[J]. Eur J Immunol， 2006， 36(8)：1994-2002.
29.	Wang T， Chen L， Ahmed E， et al. Prevention of allograft tolerance by bacterial infection with Listeria monocytogenes[J]. J Immunol， 2008， 180(9)：5991-5999.
30.	Chen L， Wang T， Zhou P， et al. TLR engagement prevents transplantation tolerance[J]. Am J Transplant， 2006， 6(10)：2282-2291.
31.	Shen H， Goldstein DR. IL-6 and TNF-α synergistically inhibitallograft acceptance[J]. J Am Soc Nephrol， 2009， 20(5)：1032-1040.
32.	Bettelli E， Oukka M， Kuchroo VK. T(H)-17 cells in the circle of immunity and autoimmunity[J]. Nat Immunol， 2007， 8(4)：345-350.
33.	Porrett PM， Yuan X， Larosa DF， et al. Mechanisms underlying blockade of allograft acceptance by TLR ligands[J]. J Immunol， 2008， 181(3)：1692-1699.
34.	Chen L， Ahmed E， Wang T， et al. TLR signals promote IL-6/IL-.
35.	Smirnova I， Hamblin MT， McBride C， et al. Excess of rare amino acid polymorphisms in the Toll-like receptor 4 in humans[J]. Genetics， 2001， 158(4)：1657-1664.
36.	Palmer SM， Burch LH， Davis RD， et al. The role of innateimmunity in acute allograft rejection after lung transplantation[J]. Am J Respir Crit Care Med， 2003， 168(6)：628-632.
37.	Ducloux D， Deschamps M， Yannaraki M， et al. Relevance of toll-like receptor-4 polymorphisms in renal transplantation[J]. Kidney Int， 2005， 67(6)：2454-2461.
38.	Krüger B， Krick S， Dhillon N， et al. Donor toll-like receptor 4 contributes to ischemia and reperfusion injury following human kidney transplantation[J]. Proc Natl Acad Sci USA， 2009， 106(9)：3390-3395.
39.	Methe H， Zimmer E， Grimm C， et al. Evidence for a role of toll-like receptor 4 in development of chronic allograft rejection after cardiac transplantation[J]. Transplantation， 2004， 78(9)：1324-1331.
40.	McDaniel DO， Zhou X， Moore CK， et al. Cardiac allograft rejection correlates with increased expressions of Toll-like receptors 2 and 4 and allograft inflammatory factor 1[J]. Transplant Proc， 2010， 42(10)：4235-4237.
41.	Citores MJ， Baños I， Noblejas A， et al. Toll-like receptor 3 L412F polymorphism may protect against acute graft rejection in adult patients undergoing liver transplantation for hepatitis C-related cirrhosis[J]. Transplant Proc， 2011， 43(6)：2224-2226.
42.	Ge X， Uzunel M， Ericzon BG， et al. Biliary epithelial cell antibodies induce expression of toll-like receptors 2 and 3：a mechanism for post-liver transplantation cholangitis?[J]. Liver Transpl， 2005， 11(8)：911-921.

1. Medzhitov R， Preston-Hurlburt P， Janeway CA Jr. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity[J]. Nature， 1997， 388(6640)：394-397.
2. Takeda K， Kaisho T， Akira S. Toll-like receptors[J]. Annu Rev Immunol， 2003， 21：335-376.
3. Asprodites N， Zheng L， Geng D， et al. Engagement of toll-like receptor-2 on cytotoxic t-lymphocytes occurs in vivo and augments antitumor activity[J]. FASEB J， 2008， 22(10)：3628-3637.
4. Lorenz E. TLR2 and TLR4 expression during bacterial infections[J]. Curr Pharm Des， 2006， 12(32)：4185-4193.
5. Boehme KW， Guerrero M， Compton T. Human cytomegalovirus envelope glycoproteins B and H are necessary for TLR2 activation in permissive cells[J]. J Immunol， 2006， 177(10)：7094-7102.
6. Krasowska-Zoladek A， Banaszewska M， Kraszpulski M， et al. Kinetics of inflammatory response of astrocytes induced by TLR3 and TLR4 ligation[J]. J Neurosci Res， 2007， 85(1)：205-212.
7. Tabeta K， Georgel P， Janssen E， et al. Toll-like receptors 9 and 3 as essential components of innate immune defense against mouse cytomegalovirus infection[J]. Proc Natl Acad Sci USA， 2004， 101(10)：3516-3521.
8. Arbour NC， Lorenz E， Schutte BC， et al. TLR4 mutations are associated with endotoxin hyporesponsiveness in humans[J]. Nat Genet， 2000， 25(2)：187-191.
9. Miyamoto Y， Iimura M， Kaper JB， et al. Role of Shiga toxin versus H7 flagellin in enterohaemorrhagic escherichia coli signa-ling of human colon epithelium in vivo[J]. Cell Microbiol， 2006， 8(5)：869-879.
10. Guan Y， Ranoa DR， Jiang S， et al. Human TLRs 10 and 1 share common mechanisms of innate immune sensing but not signaling[J]. J Immunol， 2010， 184(9)：5094-5103.
11. Lauw FN， Caffrey DR， Golenbock DT. Of mice and man：TLR11 (finally) finds profilin[J]. Trends Immunol， 2005， 26(10)：509-511.
12. Rubartelli A， Lotze MT. Inside， outside， upside down：damage-associated molecular-pattern molecules (DAMPs) and redox[J]. Trends Immunol， 2007， 28(10)：429-436.
13. Shirali AC， Goldstein DR. Activation of the innate immune system by the endogenous ligand hyaluronan[J]. Curr Opin Organ Transplant， 2008， 13(1)：20-25.
14. Tesar BM， Jiang D， Liang J， et al. The role of hyaluronan degradation products as innate alloimmune agonists[J]. Am J Transplant， 2006， 6(11)：2622-2635.
15. Pockley AG. Heat shock proteins， anti-heat shock protein reactivity and allograft rejection[J]. Transplantation， 2001， 71(11)：1503-1507.
16. Alegre ML， Goldstein DR， Chong AS. Toll-like receptor signaling in transplantation[J]. Curr Opin Organ Transplant， 2008， 13(4)：358-365.
17. Zhai Y， Qiao B， Shen XD， et al. Evidence for the pivotal role of endogenous toll-like receptor 4 ligands in liver ischemia and reperfusion injury[J]. Transplantation， 2008， 85(7)：1016-1022.
18. -dependent transplant rejection[J]. J Immunol， 2009， 182 (10)：6217-6225.
19. Beg AA. Endogenous ligands of Toll-like receptors：implications for regulating inflammatory and immune responses[J]. Trends Immunol， 2002， 23(11)：509-512.
20. O’Neill LA， Bowie AG. The family of five：TIR-domain-containing adaptors in Toll-like receptor signalling[J]. Nat Rev Immunol， 2007， 7(5)：353-364.
21. Choi YJ， Im E， Chung HK， et al. TRIF mediates Toll-likereceptor 5-induced signaling in intestinal epithelial cells[J]. J Biol Chem， 2010， 285(48)：37570-37578.
22. Choi YJ， Im E， Pothoulakis C， et al. TRIF modulates TLR5-dependent responses by inducing proteolytic degradation of TLR5[J]. J Biol Chem， 2010， 285(28)：21382-21390.
23. Liberati NT， Fitzgerald KA， Kim DH， et al. Requirement for a conserved Toll/interleukin-1 resistance domain protein in the Caenorhabditis elegans immune response[J]. Proc Natl Acad Sci USA， 2004， 101(17)：6593-6598.
24. Wald D， Qin J， Zhao Z， et al. SIGIRR， a negative regulator of Toll-like receptor-interleukin 1 receptor signaling[J]. Nat Immunol， 2003， 4(9)：920-927.
25. 朱旭辉，杨明金. CMRF35样分子对Toll样受体信号通路的影响及其机制的研究进展[J]. 中国肿瘤生物治疗杂志， 2011， 18(1)：101-104.
26. Goldstein DR， Tesar BM， Akira S， et al. Critical role of the Toll-like receptor signal adaptor protein MyD88 in acute allograft rejection[J]. J Clin Invest， 2003， 111(10)：1571-1578.
27. Tesar BM， Zhang J， Li Q， et al. TH1 immune responses to fully MHC mismatched allografts are diminished in the absence of MyD88， a toll-like receptor signal adaptor protein[J]. Am J Transplant， 2004， 4(9)：1429-1439.
28. McKay D， Shigeoka A， Rubinstein M， et al. Simultaneous deletion of MyD88 and Trif delays major histocompatibility and minor antigen mismatch allograft rejection[J]. Eur J Immunol， 2006， 36(8)：1994-2002.
29. Wang T， Chen L， Ahmed E， et al. Prevention of allograft tolerance by bacterial infection with Listeria monocytogenes[J]. J Immunol， 2008， 180(9)：5991-5999.
30. Chen L， Wang T， Zhou P， et al. TLR engagement prevents transplantation tolerance[J]. Am J Transplant， 2006， 6(10)：2282-2291.
31. Shen H， Goldstein DR. IL-6 and TNF-α synergistically inhibitallograft acceptance[J]. J Am Soc Nephrol， 2009， 20(5)：1032-1040.
32. Bettelli E， Oukka M， Kuchroo VK. T(H)-17 cells in the circle of immunity and autoimmunity[J]. Nat Immunol， 2007， 8(4)：345-350.
33. Porrett PM， Yuan X， Larosa DF， et al. Mechanisms underlying blockade of allograft acceptance by TLR ligands[J]. J Immunol， 2008， 181(3)：1692-1699.
34. Chen L， Ahmed E， Wang T， et al. TLR signals promote IL-6/IL-.
35. Smirnova I， Hamblin MT， McBride C， et al. Excess of rare amino acid polymorphisms in the Toll-like receptor 4 in humans[J]. Genetics， 2001， 158(4)：1657-1664.
36. Palmer SM， Burch LH， Davis RD， et al. The role of innateimmunity in acute allograft rejection after lung transplantation[J]. Am J Respir Crit Care Med， 2003， 168(6)：628-632.
37. Ducloux D， Deschamps M， Yannaraki M， et al. Relevance of toll-like receptor-4 polymorphisms in renal transplantation[J]. Kidney Int， 2005， 67(6)：2454-2461.
38. Krüger B， Krick S， Dhillon N， et al. Donor toll-like receptor 4 contributes to ischemia and reperfusion injury following human kidney transplantation[J]. Proc Natl Acad Sci USA， 2009， 106(9)：3390-3395.
39. Methe H， Zimmer E， Grimm C， et al. Evidence for a role of toll-like receptor 4 in development of chronic allograft rejection after cardiac transplantation[J]. Transplantation， 2004， 78(9)：1324-1331.
40. McDaniel DO， Zhou X， Moore CK， et al. Cardiac allograft rejection correlates with increased expressions of Toll-like receptors 2 and 4 and allograft inflammatory factor 1[J]. Transplant Proc， 2010， 42(10)：4235-4237.
41. Citores MJ， Baños I， Noblejas A， et al. Toll-like receptor 3 L412F polymorphism may protect against acute graft rejection in adult patients undergoing liver transplantation for hepatitis C-related cirrhosis[J]. Transplant Proc， 2011， 43(6)：2224-2226.
42. Ge X， Uzunel M， Ericzon BG， et al. Biliary epithelial cell antibodies induce expression of toll-like receptors 2 and 3：a mechanism for post-liver transplantation cholangitis?[J]. Liver Transpl， 2005， 11(8)：911-921.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Toll-Like Receptors Signaling and Research Progress of Its Role in Organ Transplantation

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