Publication in detail

Hepatology (Baltimore, Md.) 2013 Mar 4. doi: 10.1002/hep.26346. [Epub ahead of print]

Cellular specific role of toll-like receptor 4 in hepatic ischemia-reperfusion injury.

Nace, GW; Huang, H; Klune, JR; Eid, RE; Rosborough, BR; Korff, S; Li, S; Shapiro, RA; Stolz, DB; Sodhi, CP; Hackam, DJ; Geller, DA; Billiar, TR; Tsung, A

Department of Surgery, University of Pittsburgh, Pittsburgh, PA.

Abstract:
Ischemia-reperfusion (I/R) injury is a process whereby an initial hypoxic insult and subsequent return of blood flow leads to the propagation of innate immune responses and organ injury. The necessity of the pattern recognition receptor, toll-like receptor (TLR)-4, for this innate immune response has been previously shown. However, TLR4 is present on various cell types of the liver, both immune and non-immune cells. Therefore, we sought to determine the role of TLR4 in individual cell populations, specifically parenchymal hepatocytes, myeloid cells including Kupffer cells, and dendritic cells following hepatic I/R. When hepatocyte specific (Alb-TLR4-/- ) and myeloid cell specific (Lyz-TLR4-/- ) TLR4 knockout mice were subjected to warm hepatic ischemia there was significant protection in these mice compared to wild-type (WT). However, the protection afforded in these two strains was significantly less than global TLR4 knockout (TLR4-/- ) mice. Dendritic cell specific TLR4-/- (CD11c-TLR4-/- ) mice had significantly increased hepatocellular damage compared to WT mice. Circulating levels of high mobility group box-1 (HMGB1) were significantly reduced in the Alb-TLR4-/- mice compared to WT, Lyz-TLR4-/- , CD11c-TLR4-/- mice and equivalent to global TLR4-/- mice, suggesting that TLR4 mediated HMGB1 release from hepatocytes may be a source of HMGB1 after I/R. Hepatocytes exposed to hypoxia responded by rapidly phosphorylating the mitogen-activated protein kinases JNK and p38 in a TLR4-dependent manner; inhibition of JNK decreased the release of HMGB1 after both hypoxia in vitro and I/R in vivo. Conclusion: These results provide insight into the individual cellular response of TLR4. It was found that the parenchymal hepatocyte is an active participant in the sterile inflammatory response after I/R through TLR4-mediated activation of pro-inflammatory signaling and release of danger signals such as HMGB1. (HEPATOLOGY 2013.).

ยป Online Version

Proven Track Record

The team at Ozgene has over two decades of experience creating customised knockout and knock-in mice for pivotal medical research globally. Over 300 scientific publications are based on research using Ozgene mice.

Go to Publications

Global Client Base

Ozgene generates genetically customised mice for researchers around the world. Ozgene mice can be found in 31 different countries on 5 continents from small academic institutions to multinational pharmaceutical companies.

See Map

Lean Management

Ozgene is applying Lean Management principles to deliver the highest quality services and shortest lead times to our customers. The implementation of Lean Culture has already seen an improvement in our processes and timelines.

Read More