Mechanisms of toll-like receptor 4 (TLR4)-mediated inflammation after cold ischemia/reperfusion in the heart

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

Research output: Contribution to journalArticle

71 Citations (Scopus)

Abstract

BACKGROUND.: Toll-Like Receptor 4 (TLR4) signaling mediates early inflammation after cold ischemia-reperfusion (I/R). We hypothesized that the TLR4 coreceptor CD14, the intracellular adaptor proteins myeloid differentiation factor 88 (MyD88) and TIR domain-containing-adaptor inducing IFNβ (TRIF) would be required for cold I/R induced inflammation. High mobility group box 1 (HMGB1) is a putative endogenous activator of TLR4. Therefore, we also assessed the contribution of HMGB1 in cold I/R induced inflammation. METHODS.: Syngeneic heart transplants were performed in mice deficient in CD14, MyD88, TRIF, or wild-type mice. In other experiments, anti-HMGB1 neutralizing antibody or control IgG was administered at reperfusion. Donor hearts were subjected to 2 hr of cold ischemia and retrieved after 3 hr of reperfusion. RESULTS.: After cold I/R, grafts revealed striking translocation of HMGB1 out of the nucleus in cardiac myocytes. Administration of an anti-HMGB1 neutralizing antibody resulted in reduced systemic interleukin (IL)-6, tumor necrosis factor alpha (TNFα), and intercellular adhesion molecule-1 (ICAM-1) messenger RNA (mRNA) levels (Pĝ‰Currency sign0.05). Compared with controls, CD14 knock-out (KO) mice exhibited significantly lower (Pĝ‰Currency sign0.05) systemic IL-6 and JE/monocyte chemotractant protein-1 levels after cold I/R. Intragraft TNFα and IL-1β mRNA levels were also significantly lower (Pĝ‰Currency sign0.05) in CD14 KO grafts. MyD88 KO mice exhibited significantly lower (P≥0.05) systemic IL-6 levels compared with control mice after cold I/R. Intragraft TNFα, IL-6, and ICAM-1 mRNA levels were also significantly lower (Pĝ‰Currency sign0.05) in MyD88 KO grafts. Significantly lower levels (Pĝ‰Currency sign0.05) of serum IL-6, monocyte chemotractant protein-1 as well as intragraft TNFβ, IL-6, IL-1β, and ICAM-1 were observed after cold I/R in TRIF deficient animals compared with controls. CONCLUSIONS.: CD14, MyD88, TRIF, and HMGB1 contribute to the inflammatory response that occurs after cold I/R. These results provide insight into the mechanisms of TLR4-mediated inflammation after cold I/R.

Original languageEnglish
Pages (from-to)1455-1463
Number of pages9
JournalTransplantation
Volume87
Issue number10
DOIs
Publication statusPublished - May 27 2009
Externally publishedYes

Fingerprint

Cold Ischemia
Toll-Like Receptor 4
Myeloid Differentiation Factor 88
Reperfusion
Interleukin-6
Inflammation
Intercellular Adhesion Molecule-1
Tumor Necrosis Factor-alpha
Transplants
Neutralizing Antibodies
Interleukin-1
Knockout Mice
Messenger RNA
Monocytes
Proteins
Cardiac Myocytes
Immunoglobulin G
Serum

Keywords

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

ASJC Scopus subject areas

  • Transplantation

Cite this

Kaczorowski, D. J., Nakao, A., Vallabhaneni, R., Mollen, K. P., Sugimoto, R., Kohmoto, J., ... Billiar, T. R. (2009). Mechanisms of toll-like receptor 4 (TLR4)-mediated inflammation after cold ischemia/reperfusion in the heart. Transplantation, 87(10), 1455-1463. https://doi.org/10.1097/TP.0b013e3181a36e5e

Mechanisms of toll-like receptor 4 (TLR4)-mediated inflammation after cold ischemia/reperfusion in the heart. / Kaczorowski, David J.; Nakao, Atsunori; Vallabhaneni, Raghuveer; Mollen, Kevin P.; Sugimoto, Ryujiro; Kohmoto, Junichi; Zuckerbraun, Brian S.; McCurry, Kenneth R.; Billiar, Timothy R.

In: Transplantation, Vol. 87, No. 10, 27.05.2009, p. 1455-1463.

Research output: Contribution to journalArticle

Kaczorowski, DJ, Nakao, A, Vallabhaneni, R, Mollen, KP, Sugimoto, R, Kohmoto, J, Zuckerbraun, BS, McCurry, KR & Billiar, TR 2009, 'Mechanisms of toll-like receptor 4 (TLR4)-mediated inflammation after cold ischemia/reperfusion in the heart', Transplantation, vol. 87, no. 10, pp. 1455-1463. https://doi.org/10.1097/TP.0b013e3181a36e5e
Kaczorowski, David J. ; Nakao, Atsunori ; Vallabhaneni, Raghuveer ; Mollen, Kevin P. ; Sugimoto, Ryujiro ; Kohmoto, Junichi ; Zuckerbraun, Brian S. ; McCurry, Kenneth R. ; Billiar, Timothy R. / Mechanisms of toll-like receptor 4 (TLR4)-mediated inflammation after cold ischemia/reperfusion in the heart. In: Transplantation. 2009 ; Vol. 87, No. 10. pp. 1455-1463.
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AU - Nakao, Atsunori

AU - Vallabhaneni, Raghuveer

AU - Mollen, Kevin P.

AU - Sugimoto, Ryujiro

AU - Kohmoto, Junichi

AU - Zuckerbraun, Brian S.

AU - McCurry, Kenneth R.

AU - Billiar, Timothy R.

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N2 - BACKGROUND.: Toll-Like Receptor 4 (TLR4) signaling mediates early inflammation after cold ischemia-reperfusion (I/R). We hypothesized that the TLR4 coreceptor CD14, the intracellular adaptor proteins myeloid differentiation factor 88 (MyD88) and TIR domain-containing-adaptor inducing IFNβ (TRIF) would be required for cold I/R induced inflammation. High mobility group box 1 (HMGB1) is a putative endogenous activator of TLR4. Therefore, we also assessed the contribution of HMGB1 in cold I/R induced inflammation. METHODS.: Syngeneic heart transplants were performed in mice deficient in CD14, MyD88, TRIF, or wild-type mice. In other experiments, anti-HMGB1 neutralizing antibody or control IgG was administered at reperfusion. Donor hearts were subjected to 2 hr of cold ischemia and retrieved after 3 hr of reperfusion. RESULTS.: After cold I/R, grafts revealed striking translocation of HMGB1 out of the nucleus in cardiac myocytes. Administration of an anti-HMGB1 neutralizing antibody resulted in reduced systemic interleukin (IL)-6, tumor necrosis factor alpha (TNFα), and intercellular adhesion molecule-1 (ICAM-1) messenger RNA (mRNA) levels (Pĝ‰Currency sign0.05). Compared with controls, CD14 knock-out (KO) mice exhibited significantly lower (Pĝ‰Currency sign0.05) systemic IL-6 and JE/monocyte chemotractant protein-1 levels after cold I/R. Intragraft TNFα and IL-1β mRNA levels were also significantly lower (Pĝ‰Currency sign0.05) in CD14 KO grafts. MyD88 KO mice exhibited significantly lower (P≥0.05) systemic IL-6 levels compared with control mice after cold I/R. Intragraft TNFα, IL-6, and ICAM-1 mRNA levels were also significantly lower (Pĝ‰Currency sign0.05) in MyD88 KO grafts. Significantly lower levels (Pĝ‰Currency sign0.05) of serum IL-6, monocyte chemotractant protein-1 as well as intragraft TNFβ, IL-6, IL-1β, and ICAM-1 were observed after cold I/R in TRIF deficient animals compared with controls. CONCLUSIONS.: CD14, MyD88, TRIF, and HMGB1 contribute to the inflammatory response that occurs after cold I/R. These results provide insight into the mechanisms of TLR4-mediated inflammation after cold I/R.

AB - BACKGROUND.: Toll-Like Receptor 4 (TLR4) signaling mediates early inflammation after cold ischemia-reperfusion (I/R). We hypothesized that the TLR4 coreceptor CD14, the intracellular adaptor proteins myeloid differentiation factor 88 (MyD88) and TIR domain-containing-adaptor inducing IFNβ (TRIF) would be required for cold I/R induced inflammation. High mobility group box 1 (HMGB1) is a putative endogenous activator of TLR4. Therefore, we also assessed the contribution of HMGB1 in cold I/R induced inflammation. METHODS.: Syngeneic heart transplants were performed in mice deficient in CD14, MyD88, TRIF, or wild-type mice. In other experiments, anti-HMGB1 neutralizing antibody or control IgG was administered at reperfusion. Donor hearts were subjected to 2 hr of cold ischemia and retrieved after 3 hr of reperfusion. RESULTS.: After cold I/R, grafts revealed striking translocation of HMGB1 out of the nucleus in cardiac myocytes. Administration of an anti-HMGB1 neutralizing antibody resulted in reduced systemic interleukin (IL)-6, tumor necrosis factor alpha (TNFα), and intercellular adhesion molecule-1 (ICAM-1) messenger RNA (mRNA) levels (Pĝ‰Currency sign0.05). Compared with controls, CD14 knock-out (KO) mice exhibited significantly lower (Pĝ‰Currency sign0.05) systemic IL-6 and JE/monocyte chemotractant protein-1 levels after cold I/R. Intragraft TNFα and IL-1β mRNA levels were also significantly lower (Pĝ‰Currency sign0.05) in CD14 KO grafts. MyD88 KO mice exhibited significantly lower (P≥0.05) systemic IL-6 levels compared with control mice after cold I/R. Intragraft TNFα, IL-6, and ICAM-1 mRNA levels were also significantly lower (Pĝ‰Currency sign0.05) in MyD88 KO grafts. Significantly lower levels (Pĝ‰Currency sign0.05) of serum IL-6, monocyte chemotractant protein-1 as well as intragraft TNFβ, IL-6, IL-1β, and ICAM-1 were observed after cold I/R in TRIF deficient animals compared with controls. CONCLUSIONS.: CD14, MyD88, TRIF, and HMGB1 contribute to the inflammatory response that occurs after cold I/R. These results provide insight into the mechanisms of TLR4-mediated inflammation after cold I/R.

KW - Cold storage

KW - Inflammation

KW - Ischemia-reperfusion

KW - Toll-like receptors

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