To the Editor:

We read with great interest the article by Kamo et al.[1] 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.[2]

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.[3] 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.[1] 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.[1] 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.[4] 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


  1. Top of page
  2. References
  • 1
    Kamo N, Ke B, Ghaffari AA, Busuttil RW, Cheng G, Kupiec-Weglinski JW. The ASC/Caspase-1/IL-1beta signaling triggers inflammatory responses by promoting HMGB1 induction in liver ischemia-reperfusion injury. Hepatology 2013;58:351-362.
  • 2
    Kawaguchi M, Takahashi M, Hata T, Kashima Y, Usui F, Morimoto H, et al. Inflammasome activation of cardiac fibroblasts is essential for myocardial ischemia/reperfusion injury. Circulation 2011;123:594-604.
  • 3
    Shigeoka AA, Mueller JL, Kambo A, Mathison JC, King AJ, Hall WF, Correia Jda S, et al. An inflammasome-independent role for epithelial-expressed Nlrp3 in renal ischemia-reperfusion injury. J Immunol 2010;185:6277-6285.
  • 4
    Kato A, Gabay C, Okaya T, Lentsch AB. Specific role of interleukin-1 in hepatic neutrophil recruitment after ischemia/reperfusion. Am J Pathol 2002;161:1797-1803.