Hepatic ischemia/reperfusion injury involves functional TLR4 signaling in nonparenchymal cells

Allan Tsung, Rosemary A. Hoffman, Kunihiko Izuishi, Nathan D. Critchlow, Atsunori Nakao, Meagan H. Chan, Michael T. Lotze, David A. Geller, Timothy R. Billiar

Research output: Contribution to journalArticle

299 Citations (Scopus)

Abstract

Endogenous ligands from damaged cells, so-called damage-associated molecular pattern molecules, can activate innate immunity via TLR4 signaling. Hepatic warm ischemia and reperfusion (I/R) injury and inflammation is largely TLR4 dependent. We produced TLR4 chimeric mice to assess whether the TLR4-dependent injury required TLR4 expression on liver parenchymal or nonparenchymal cells. Chimeric mice were produced by adoptive transfer of donor bone marrow cells into irradiated recipient animals using reciprocal combinations of TLR4 wild-type (WT; C3H/HeOuj) and TLR4 mutant (C3H/HeJ) mouse bone marrow. Wild-type chimeric mice bearing TLR4 mutant hemopoietic cells and TLR4 mutant mice transplanted with their own bone marrow-derived cells were protected from hepatic I/R and exhibited decreased JNK and NF-κB activation compared with WT chimeric mice transplanted with their own bone marrow. In contrast, TLR4 mutant mice transplanted with TLR4 WT bone marrow were not protected from liver I/R and demonstrated pronounced increases in JNK and NF-κB activation when compared with autochthonous transplanted mutant mice. In addition, depletion of phagocytes taking up gadolinium chloride failed to provide any additional protection to TLR4 mutant mice, but substantially reduced damage in WT mice after hepatic I/R. Together, these results demonstrate that TLR4 engagement on actively phagocytic nonparenchymal cells such as Kupffer cells is required for warm I/R-induced injury and inflammation in the liver.

Original languageEnglish
Pages (from-to)7661-7668
Number of pages8
JournalJournal of Immunology
Volume175
Issue number11
Publication statusPublished - Dec 1 2005
Externally publishedYes

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Reperfusion Injury
Liver
Warm Ischemia
Bone Marrow
Phagocytes
Bone Marrow Cells
Reperfusion
Ischemia
Inflammation
Kupffer Cells
Adoptive Transfer
Innate Immunity
Ligands
Wounds and Injuries

ASJC Scopus subject areas

  • Immunology

Cite this

Tsung, A., Hoffman, R. A., Izuishi, K., Critchlow, N. D., Nakao, A., Chan, M. H., ... Billiar, T. R. (2005). Hepatic ischemia/reperfusion injury involves functional TLR4 signaling in nonparenchymal cells. Journal of Immunology, 175(11), 7661-7668.

Hepatic ischemia/reperfusion injury involves functional TLR4 signaling in nonparenchymal cells. / Tsung, Allan; Hoffman, Rosemary A.; Izuishi, Kunihiko; Critchlow, Nathan D.; Nakao, Atsunori; Chan, Meagan H.; Lotze, Michael T.; Geller, David A.; Billiar, Timothy R.

In: Journal of Immunology, Vol. 175, No. 11, 01.12.2005, p. 7661-7668.

Research output: Contribution to journalArticle

Tsung, A, Hoffman, RA, Izuishi, K, Critchlow, ND, Nakao, A, Chan, MH, Lotze, MT, Geller, DA & Billiar, TR 2005, 'Hepatic ischemia/reperfusion injury involves functional TLR4 signaling in nonparenchymal cells', Journal of Immunology, vol. 175, no. 11, pp. 7661-7668.
Tsung A, Hoffman RA, Izuishi K, Critchlow ND, Nakao A, Chan MH et al. Hepatic ischemia/reperfusion injury involves functional TLR4 signaling in nonparenchymal cells. Journal of Immunology. 2005 Dec 1;175(11):7661-7668.
Tsung, Allan ; Hoffman, Rosemary A. ; Izuishi, Kunihiko ; Critchlow, Nathan D. ; Nakao, Atsunori ; Chan, Meagan H. ; Lotze, Michael T. ; Geller, David A. ; Billiar, Timothy R. / Hepatic ischemia/reperfusion injury involves functional TLR4 signaling in nonparenchymal cells. In: Journal of Immunology. 2005 ; Vol. 175, No. 11. pp. 7661-7668.
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