MyD88 and Trif Signaling Play Distinct Roles in Cardiac Dysfunction and Mortality During Endotoxin Shock and Polymicrobial Sepsis

Overview

Journal Anesthesiology

Specialty Anesthesiology

Date 2011 Jul 28

PMID 21792053

Citations 34

Authors

Yan Feng

Lin Zou

Ming Zhang

Yan Li

Chan Chen

Wei Chao

Affiliations

Soon will be listed here.

Abstract

Background: Toll-like receptors (TLRs) such as TLR2, TLR4, and TLR9 contribute to the pathogenesis of polymicrobial sepsis. These TLRs signal via the common myeloid differentiation factor 88 (MyD88)-dependent pathways. TLR4 also signals through MyD88-independent but TIR domain-containing adaptor inducing interferon-β-mediated transcription factor (Trif)-dependent pathway. The role of the two signaling pathways in cardiac dysfunction during polymicrobial sepsis and endotoxin shock is unknown.

Methods: Sepsis was generated by cecum ligation and puncture. Mice were divided into sham and cecum ligation and puncture groups or subjected to saline or endotoxin. Left ventricular function was assessed in a Langendorff apparatus or by echocardiography. Cytokines were examined using a multiplex immunoassay. Neutrophil migratory and phagocytic functions were assessed using flow cytometry.

Results: In comparison with wild-type mice, MyD88(-/-) but not Trif(-/-) mice had markedly improved cardiac function and survival after cecum ligation and puncture. In comparison, both MyD88(-/-) and Trif(-/-) mice were protected from cardiac depression and mortality during endotoxin shock. Septic MyD88(-/-) but not Trif(-/-) mice had diminished cytokine production in serum and in peritoneal space in comparison with wild-type mice after cecum ligation and puncture. In contrast, both MyD88(-/-) and Trif(-/-) mice had attenuated serum cytokines in comparison with wild-type mice after endotoxin challenge. Neither MyD88(-/-) nor Trif(-/-) signaling had any effect on neutrophil phagocytic function or bacterial clearance at 24 h of polymicrobial sepsis.

Conclusions: These studies establish that MyD88 but not Trif signaling plays a critical role in mediating cardiac dysfunction, systemic inflammation, and mortality during polymicrobial sepsis. Both MyD88 and Trif are essential for cardiac depression and mortality during endotoxin shock.

Citing Articles

TLR4 Inhibition Attenuated LPS-Induced Proinflammatory Signaling and Cytokine Release in Mouse Hearts and Cardiomyocytes.

Wiger C, Ranheim T, Arnesen H, Vaage J, Pischke S, Yndestad A Immun Inflamm Dis. 2025; 13(1):e70133.

PMID: 39853914 PMC: 11760985. DOI: 10.1002/iid3.70133.

Extracellular vesicles in sepsis plasma mediate neuronal inflammation in the brain through miRNAs and innate immune signaling.

Park C, Lei Z, Li Y, Ren B, He J, Huang H J Neuroinflammation. 2024; 21(1):252.

PMID: 39375720 PMC: 11460013. DOI: 10.1186/s12974-024-03250-0.

CASP-Model Sepsis Triggers Systemic Innate Immune Responses Revealed by the Systems-Level Signaling Pathways.

Ai H, Li B, Meng F, Ai Y Front Immunol. 2022; 13:907646.

PMID: 35774781 PMC: 9238352. DOI: 10.3389/fimmu.2022.907646.

miR-340-5p Alleviates Oxidative Stress Injury by Targeting MyD88 in Sepsis-Induced Cardiomyopathy.

Zhang C, Zeng L, Cai G, Zhu Y, Xiong Y, Zhan H Oxid Med Cell Longev. 2022; 2022:2939279.

PMID: 35571255 PMC: 9095363. DOI: 10.1155/2022/2939279.

Epigenomic and transcriptomic analyses reveal differences between low-grade inflammation and severe exhaustion in LPS-challenged murine monocytes.

Naler L, Hsieh Y, Geng S, Zhou Z, Li L, Lu C Commun Biol. 2022; 5(1):102.

PMID: 35091696 PMC: 8799722. DOI: 10.1038/s42003-022-03035-2.

References

Plitas G, Burt B, Nguyen H, Bamboat Z, DeMatteo R . Toll-like receptor 9 inhibition reduces mortality in polymicrobial sepsis. J Exp Med. 2008; 205(6):1277-83. PMC: 2413026. DOI: 10.1084/jem.20080162. View

Medzhitov R . Toll-like receptors and innate immunity. Nat Rev Immunol. 2002; 1(2):135-45. DOI: 10.1038/35100529. View

Knuefermann P, Sakata Y, Scott Baker J, Huang C, Sekiguchi K, Hardarson H . Toll-like receptor 2 mediates Staphylococcus aureus-induced myocardial dysfunction and cytokine production in the heart. Circulation. 2004; 110(24):3693-8. DOI: 10.1161/01.CIR.0000143081.13042.04. View

Weighardt H, Kaiser-Moore S, Vabulas R, Kirschning C, Wagner H, Holzmann B . Cutting edge: myeloid differentiation factor 88 deficiency improves resistance against sepsis caused by polymicrobial infection. J Immunol. 2002; 169(6):2823-7. DOI: 10.4049/jimmunol.169.6.2823. View

Nemoto S, Vallejo J, Knuefermann P, Misra A, DeFreitas G, Carabello B . Escherichia coli LPS-induced LV dysfunction: role of toll-like receptor-4 in the adult heart. Am J Physiol Heart Circ Physiol. 2002; 282(6):H2316-23. DOI: 10.1152/ajpheart.00763.2001. View

Hotchkiss R, Coopersmith C, McDunn J, Ferguson T . The sepsis seesaw: tilting toward immunosuppression. Nat Med. 2009; 15(5):496-7. PMC: 3786779. DOI: 10.1038/nm0509-496. View

Akira S, Uematsu S, Takeuchi O . Pathogen recognition and innate immunity. Cell. 2006; 124(4):783-801. DOI: 10.1016/j.cell.2006.02.015. View

Albiger B, Dahlberg S, Sandgren A, Wartha F, Beiter K, Katsuragi H . Toll-like receptor 9 acts at an early stage in host defence against pneumococcal infection. Cell Microbiol. 2006; 9(3):633-44. DOI: 10.1111/j.1462-5822.2006.00814.x. View

Peck-Palmer O, Unsinger J, Chang K, Davis C, McDunn J, Hotchkiss R . Deletion of MyD88 markedly attenuates sepsis-induced T and B lymphocyte apoptosis but worsens survival. J Leukoc Biol. 2008; 83(4):1009-18. DOI: 10.1189/jlb.0807528. View

10.

Albiger B, Dahlberg S, Henriques-Normark B, Normark S . Role of the innate immune system in host defence against bacterial infections: focus on the Toll-like receptors. J Intern Med. 2007; 261(6):511-28. DOI: 10.1111/j.1365-2796.2007.01821.x. View

11.

Yamamoto M, Sato S, Hemmi H, Hoshino K, Kaisho T, Sanjo H . Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway. Science. 2003; 301(5633):640-3. DOI: 10.1126/science.1087262. View

12.

Angus D, Lidicker J, Clermont G, Carcillo J, Pinsky M . Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med. 2001; 29(7):1303-10. DOI: 10.1097/00003246-200107000-00002. View

13.

Uematsu S, Akira S . Toll-like receptors and Type I interferons. J Biol Chem. 2007; 282(21):15319-23. DOI: 10.1074/jbc.R700009200. View

14.

Echtenacher B, Freudenberg M, Jack R, Mannel D . Differences in innate defense mechanisms in endotoxemia and polymicrobial septic peritonitis. Infect Immun. 2001; 69(12):7271-6. PMC: 98811. DOI: 10.1128/IAI.69.12.7172-7276.2001. View

15.

Alves-Filho J, de Freitas A, Russo M, Cunha F . Toll-like receptor 4 signaling leads to neutrophil migration impairment in polymicrobial sepsis. Crit Care Med. 2006; 34(2):461-70. DOI: 10.1097/01.ccm.0000198527.71819.e1. View

16.

Negishi H, Osawa T, Ogami K, Ouyang X, Sakaguchi S, Koshiba R . A critical link between Toll-like receptor 3 and type II interferon signaling pathways in antiviral innate immunity. Proc Natl Acad Sci U S A. 2008; 105(51):20446-51. PMC: 2629334. DOI: 10.1073/pnas.0810372105. View

17.

Feng Y, Zhao H, Xu X, Buys E, Raher M, Bopassa J . Innate immune adaptor MyD88 mediates neutrophil recruitment and myocardial injury after ischemia-reperfusion in mice. Am J Physiol Heart Circ Physiol. 2008; 295(3):H1311-H1318. PMC: 2544501. DOI: 10.1152/ajpheart.00119.2008. View

18.

Roger T, Froidevaux C, Le Roy D, Reymond M, Chanson A, Mauri D . Protection from lethal gram-negative bacterial sepsis by targeting Toll-like receptor 4. Proc Natl Acad Sci U S A. 2009; 106(7):2348-52. PMC: 2650125. DOI: 10.1073/pnas.0808146106. View

19.

Kelly-Scumpia K, Scumpia P, Delano M, Weinstein J, Cuenca A, Wynn J . Type I interferon signaling in hematopoietic cells is required for survival in mouse polymicrobial sepsis by regulating CXCL10. J Exp Med. 2010; 207(2):319-26. PMC: 2822595. DOI: 10.1084/jem.20091959. View

20.

Bozic C, Kolakowski Jr L, Gerard N, Garcia-Rodriguez C, Conklyn M, Breslow R . Expression and biologic characterization of the murine chemokine KC. J Immunol. 1995; 154(11):6048-57. View