Potential conflict of interest: Nothing to report.
Role of the inflammasome in inflammatory responses and subsequent injury after hepatic ischemia-reperfusion injury
Article first published online: 10 OCT 2013
© 2013 by the American Association for the Study of Liver Diseases
Volume 58, Issue 6, page 2212, December 2013
How to Cite
Inoue, Y., Yasuda, Y. and Takahashi, M. (2013), Role of the inflammasome in inflammatory responses and subsequent injury after hepatic ischemia-reperfusion injury. Hepatology, 58: 2212. doi: 10.1002/hep.26480
- Issue published online: 26 NOV 2013
- Article first published online: 10 OCT 2013
- Accepted manuscript online: 21 MAY 2013 08:11AM EST
- Manuscript Accepted: 24 MAR 2013
- Manuscript Received: 18 MAR 2013
To the Editor:
We read with great interest the article by Kamo et al. in which the authors showed that after hepatic ischemia-reperfusion (I/R) injury, inflammasome activation mediated by apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) leads to interleukin-1β (IL-1β) production and subsequently promotes high mobility group box 1(HMGB1) induction, which triggers a Toll-like receptor 4 (TLR4)-driven inflammatory response. Consistent with their findings, we recently showed that ASC-mediated inflammasome activation plays an essential role in the initial inflammatory response after myocardial I/R injury.
Recently, it has been shown that inflammasome components such as ASC and NLR family pyrin domain containing 3 (NLRP3) can function independently of inflammasomes. Shigeoka et al. showed that mice deficient in NLRP3 but not ASC or caspase-1 had reduced renal I/R. Because the inflammasome is defined as a molecular platform that induces caspase-1 activation, they concluded that an NLRP3-dependent and inflammasome-independent pathway contributed to the development of I/R injury in the kidney. Similar to their findings, we observed that hepatic I/R injury was significantly ameliorated in mice deficient for NLRP3 but not ASC. This was inconsistent with the finding of Kamo et al. Although the reason for this discrepancy is unclear, the differences between our study and Kamo et al.'s study are the hepatic I/R protocol used and the extent of injury. We subjected C57BL/6 wild-type mice to hepatic I/R with 60 minutes ischemia of the left lateral and median lobes (i.e., interruption of the hepatic artery and portal vein) followed by a 6-hour reperfusion, whereas Kamo et al. subjected mice to I/R with 90 minutes ischemia followed by a 6-hour reperfusion. Serum alanine transaminase (ALT) levels increased to ∼5,000 IU/mL in our model and 33,000 IU/mL in the model of Kamo et al. Moreover, regarding the role of IL-1β, Kato et al. reported that there was no difference in serum ALT levels between wild-type and IL-1 receptor-deficient mice after hepatic I/R injury and suggested a limited role of IL-1β in causing hepatic I/R injury.
We agree with the authors' conclusion that the inflammasome plays a substantial role in hepatic I/R injury; however, the contribution of the inflammasome depends on the extent of injury and status of inflammatory responses; therefore, researchers should be aware of experimental disease conditions to discern the precise role of the inflammasome.
Yoshiyuki Inoue, M.D.1,2
Yoshikazu Yasuda, M.D., Ph.D.2
Masafumi Takahashi, M.D., Ph.D.1
1Division of Inflammation Research, Center for Molecular Medicine, Tochigi, Japan
2Department of Surgery, Jichi Medical University, Tochigi, Japan