Toll-like receptor 4 mediates the early inflammatory response after cold ischemia/reperfusion

David J. Kaczorowski, Atsunori Nakao, Kevin P. Mollen, Raghuveer Vallabhaneni, Ryujiro Sugimoto, Junichi Kohmoto, Kimimasa Tobita, Brian S. Zuckerbraun, Kenneth R. McCurry, Noriko Murase, Timothy R. Billiar

Research output: Contribution to journalArticle

58 Citations (Scopus)

Abstract

BACKGROUND. Ischemia/reperfusion (I/R) injury leads to graft dysfunction and may contribute to alloimmune responses posttransplantation. The molecular mechanisms of cold I/R injury are only partially characterized but may involve toll-like receptor (TLR)-4 activation by endogenous ligands. We tested the hypothesis that TLR4 mediates the early inflammatory response in the setting of cold I/R in a murine cardiac transplant model. METHODS. Syngeneic heart transplants were performed in mutant mice deficient in TLR4 signaling (C3H/HeJ) and wild-type mice (C3H/HeOuJ). Transplants were also performed between the strains (mutant hearts into wild-type recipients and the converse). Donor hearts were subjected to 2 hr of cold ischemia. The grafts were retrieved at 3 and 24 hr after reperfusion. Serum samples were collected for cytokine analysis. Reverse-transcription polymerase chain reaction and histologic analysis were used to assess intra-graft inflammation. RESULTS. After transplant, serum tumor necrosis factor (TNF), interleukin (IL)-6, JE/monocyte chemotractant protein (MCP)-1, IL-1β, and troponin I levels, as well as intragraft TNF, IL-1β, IL-6, early growth response (EGR)-1, intercellular adhesion molecule (ICAM)-1, and inducible nitric oxide synthase (iNOS) mRNA levels, were significantly lower in the mutant→mutant group compared to the wild-type→wild-type group (P≤0.05). Intermediate levels of serum IL-6, JE/MCP-1, as well as intragraft TNF, IL-1β, IL-6, and ICAM-1 mRNA were observed after transplants in the mutant→wild-type and wild- type→mutant groups. Immunohistochemistry revealed less myocardial nuclear factor-κB nuclear translocation at and less neutrophil infiltration in the mutant→mutant group compared to the wild-type→wild-type group. CONCLUSIONS. These findings demonstrate that TLR4 signaling is central to both the systemic and intragraft inflammatory responses that occur after cold I/R in the setting of organ transplantation and that TLR4 signaling on both donor and recipient cells contributes to this response.

Original languageEnglish
Pages (from-to)1279-1287
Number of pages9
JournalTransplantation
Volume84
Issue number10
DOIs
Publication statusPublished - Nov 2007
Externally publishedYes

Fingerprint

Cold Ischemia
Toll-Like Receptor 4
Reperfusion
Transplants
Interleukin-1
Interleukin-6
Tumor Necrosis Factor-alpha
Intercellular Adhesion Molecule-1
Reperfusion Injury
Monocytes
Serum
Messenger RNA
Troponin I
Neutrophil Infiltration
Inbred C3H Mouse
Organ Transplantation
Nitric Oxide Synthase Type II
Reverse Transcription
Proteins
Immunohistochemistry

Keywords

  • Cold storage
  • Inflammation
  • Ischemia/reperfusion
  • Toll-like receptors
  • Transplant

ASJC Scopus subject areas

  • Transplantation
  • Immunology

Cite this

Kaczorowski, D. J., Nakao, A., Mollen, K. P., Vallabhaneni, R., Sugimoto, R., Kohmoto, J., ... Billiar, T. R. (2007). Toll-like receptor 4 mediates the early inflammatory response after cold ischemia/reperfusion. Transplantation, 84(10), 1279-1287. https://doi.org/10.1097/01.tp.0000287597.87571.17

Toll-like receptor 4 mediates the early inflammatory response after cold ischemia/reperfusion. / Kaczorowski, David J.; Nakao, Atsunori; Mollen, Kevin P.; Vallabhaneni, Raghuveer; Sugimoto, Ryujiro; Kohmoto, Junichi; Tobita, Kimimasa; Zuckerbraun, Brian S.; McCurry, Kenneth R.; Murase, Noriko; Billiar, Timothy R.

In: Transplantation, Vol. 84, No. 10, 11.2007, p. 1279-1287.

Research output: Contribution to journalArticle

Kaczorowski, DJ, Nakao, A, Mollen, KP, Vallabhaneni, R, Sugimoto, R, Kohmoto, J, Tobita, K, Zuckerbraun, BS, McCurry, KR, Murase, N & Billiar, TR 2007, 'Toll-like receptor 4 mediates the early inflammatory response after cold ischemia/reperfusion', Transplantation, vol. 84, no. 10, pp. 1279-1287. https://doi.org/10.1097/01.tp.0000287597.87571.17
Kaczorowski, David J. ; Nakao, Atsunori ; Mollen, Kevin P. ; Vallabhaneni, Raghuveer ; Sugimoto, Ryujiro ; Kohmoto, Junichi ; Tobita, Kimimasa ; Zuckerbraun, Brian S. ; McCurry, Kenneth R. ; Murase, Noriko ; Billiar, Timothy R. / Toll-like receptor 4 mediates the early inflammatory response after cold ischemia/reperfusion. In: Transplantation. 2007 ; Vol. 84, No. 10. pp. 1279-1287.
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abstract = "BACKGROUND. Ischemia/reperfusion (I/R) injury leads to graft dysfunction and may contribute to alloimmune responses posttransplantation. The molecular mechanisms of cold I/R injury are only partially characterized but may involve toll-like receptor (TLR)-4 activation by endogenous ligands. We tested the hypothesis that TLR4 mediates the early inflammatory response in the setting of cold I/R in a murine cardiac transplant model. METHODS. Syngeneic heart transplants were performed in mutant mice deficient in TLR4 signaling (C3H/HeJ) and wild-type mice (C3H/HeOuJ). Transplants were also performed between the strains (mutant hearts into wild-type recipients and the converse). Donor hearts were subjected to 2 hr of cold ischemia. The grafts were retrieved at 3 and 24 hr after reperfusion. Serum samples were collected for cytokine analysis. Reverse-transcription polymerase chain reaction and histologic analysis were used to assess intra-graft inflammation. RESULTS. After transplant, serum tumor necrosis factor (TNF), interleukin (IL)-6, JE/monocyte chemotractant protein (MCP)-1, IL-1β, and troponin I levels, as well as intragraft TNF, IL-1β, IL-6, early growth response (EGR)-1, intercellular adhesion molecule (ICAM)-1, and inducible nitric oxide synthase (iNOS) mRNA levels, were significantly lower in the mutant→mutant group compared to the wild-type→wild-type group (P≤0.05). Intermediate levels of serum IL-6, JE/MCP-1, as well as intragraft TNF, IL-1β, IL-6, and ICAM-1 mRNA were observed after transplants in the mutant→wild-type and wild- type→mutant groups. Immunohistochemistry revealed less myocardial nuclear factor-κB nuclear translocation at and less neutrophil infiltration in the mutant→mutant group compared to the wild-type→wild-type group. CONCLUSIONS. These findings demonstrate that TLR4 signaling is central to both the systemic and intragraft inflammatory responses that occur after cold I/R in the setting of organ transplantation and that TLR4 signaling on both donor and recipient cells contributes to this response.",
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AU - Vallabhaneni, Raghuveer

AU - Sugimoto, Ryujiro

AU - Kohmoto, Junichi

AU - Tobita, Kimimasa

AU - Zuckerbraun, Brian S.

AU - McCurry, Kenneth R.

AU - Murase, Noriko

AU - Billiar, Timothy R.

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N2 - BACKGROUND. Ischemia/reperfusion (I/R) injury leads to graft dysfunction and may contribute to alloimmune responses posttransplantation. The molecular mechanisms of cold I/R injury are only partially characterized but may involve toll-like receptor (TLR)-4 activation by endogenous ligands. We tested the hypothesis that TLR4 mediates the early inflammatory response in the setting of cold I/R in a murine cardiac transplant model. METHODS. Syngeneic heart transplants were performed in mutant mice deficient in TLR4 signaling (C3H/HeJ) and wild-type mice (C3H/HeOuJ). Transplants were also performed between the strains (mutant hearts into wild-type recipients and the converse). Donor hearts were subjected to 2 hr of cold ischemia. The grafts were retrieved at 3 and 24 hr after reperfusion. Serum samples were collected for cytokine analysis. Reverse-transcription polymerase chain reaction and histologic analysis were used to assess intra-graft inflammation. RESULTS. After transplant, serum tumor necrosis factor (TNF), interleukin (IL)-6, JE/monocyte chemotractant protein (MCP)-1, IL-1β, and troponin I levels, as well as intragraft TNF, IL-1β, IL-6, early growth response (EGR)-1, intercellular adhesion molecule (ICAM)-1, and inducible nitric oxide synthase (iNOS) mRNA levels, were significantly lower in the mutant→mutant group compared to the wild-type→wild-type group (P≤0.05). Intermediate levels of serum IL-6, JE/MCP-1, as well as intragraft TNF, IL-1β, IL-6, and ICAM-1 mRNA were observed after transplants in the mutant→wild-type and wild- type→mutant groups. Immunohistochemistry revealed less myocardial nuclear factor-κB nuclear translocation at and less neutrophil infiltration in the mutant→mutant group compared to the wild-type→wild-type group. CONCLUSIONS. These findings demonstrate that TLR4 signaling is central to both the systemic and intragraft inflammatory responses that occur after cold I/R in the setting of organ transplantation and that TLR4 signaling on both donor and recipient cells contributes to this response.

AB - BACKGROUND. Ischemia/reperfusion (I/R) injury leads to graft dysfunction and may contribute to alloimmune responses posttransplantation. The molecular mechanisms of cold I/R injury are only partially characterized but may involve toll-like receptor (TLR)-4 activation by endogenous ligands. We tested the hypothesis that TLR4 mediates the early inflammatory response in the setting of cold I/R in a murine cardiac transplant model. METHODS. Syngeneic heart transplants were performed in mutant mice deficient in TLR4 signaling (C3H/HeJ) and wild-type mice (C3H/HeOuJ). Transplants were also performed between the strains (mutant hearts into wild-type recipients and the converse). Donor hearts were subjected to 2 hr of cold ischemia. The grafts were retrieved at 3 and 24 hr after reperfusion. Serum samples were collected for cytokine analysis. Reverse-transcription polymerase chain reaction and histologic analysis were used to assess intra-graft inflammation. RESULTS. After transplant, serum tumor necrosis factor (TNF), interleukin (IL)-6, JE/monocyte chemotractant protein (MCP)-1, IL-1β, and troponin I levels, as well as intragraft TNF, IL-1β, IL-6, early growth response (EGR)-1, intercellular adhesion molecule (ICAM)-1, and inducible nitric oxide synthase (iNOS) mRNA levels, were significantly lower in the mutant→mutant group compared to the wild-type→wild-type group (P≤0.05). Intermediate levels of serum IL-6, JE/MCP-1, as well as intragraft TNF, IL-1β, IL-6, and ICAM-1 mRNA were observed after transplants in the mutant→wild-type and wild- type→mutant groups. Immunohistochemistry revealed less myocardial nuclear factor-κB nuclear translocation at and less neutrophil infiltration in the mutant→mutant group compared to the wild-type→wild-type group. CONCLUSIONS. These findings demonstrate that TLR4 signaling is central to both the systemic and intragraft inflammatory responses that occur after cold I/R in the setting of organ transplantation and that TLR4 signaling on both donor and recipient cells contributes to this response.

KW - Cold storage

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KW - Ischemia/reperfusion

KW - Toll-like receptors

KW - Transplant

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