Constitutive NLRP3 activation: Too much of a bad thing

I t is widely recognized that there is a weak adaptive immune response to hepatic antigens, resulting in suboptimal T-cell priming, persistence of hepatotropic pathogens, and relative tolerance of liver allografts. Less emphasized is the fact that the liver possesses a strong innate immune inflammatory response. This is seen experimentally and clinically with liver inflammation due to toxic and metabolic stress, sepsis, and ischemia. The hepatic inflammatory response is much stronger than in other organs given a comparable insult, which gives understanding of it great importance. The cytosolic sensor NLR family pyrin domain containing 3 (NLRP3) is required for the development of inflammation and fibrosis in response to a diverse range of insults in many organs. Demonstration of a role for the NLRP3 inflammasome in the liver has kept up with the fast pace of discoveries in the field of inflammasome biology, and in the case of fibrosis has preceded findings in other organs. The NLRP3 inflammasome has now been demonstrated to have an important role by multiple groups in inflammatory conditions including drug-induced liver injury (DILI), alcoholic steatohepatitis (ASH), nonalcoholic steatohepatitis (NASH), fibrosis, and ischemia reperfusion, which is consistent with its role in other organs. In this issue Wree et al. add an important dataset to this topic by demonstrating that mice expressing a constitutively active form of NLRP3 under control of the endogenous NLRP3 promoter develop extensive liver inflammation, hepatocyte pyroptosis, stellate cell activation, and liver fibrosis. The studies in the liver to date have examined NLRP3-deficient mice, and have informed us that NLRP3 is necessary for hepatic inflammation and fibrosis. They do not inform us of the developmental stage when NLRP3 is required, the cell type it is required in, or even if it is directly required or simply provides a necessary cellular environment for inflammation to occur. The dataset from Wree et al. completes the argument by demonstrating that NLRP3 is not only required for hepatic inflammation and fibrosis, but that NLRP3 activation is sufficient for hepatic inflammation and fibrosis. This is very important for a number of reasons. First, Wree et al. use a different experimental approach to reach the same conclusions as the earlier studies. Particular experimental models and specific human diseases will clearly still need to be evaluated on an individual basis, but these findings remove any doubt about the importance of NLRP3 in the general phenomenon of hepatic inflammation and fibrosis. Additional importance of their findings is due to the fact that very large number of stimuli can activate NLRP3. These include changes in extracellular adenosine triphosphate (ATP), Ca, oxidative stress, metabolic stress, fatty acids, and places NLRP3 in the path of ASH and NASH pathogenesis. The current study details the development of liver pathology in total body constitutively active NLRP3 mice. Such broad NLRP3 activation results in a systemic inflammatory phenotype which in addition to liver pathology includes neutrophilia and inflammation in many tissues, including the skin and large joints. The systemic inflammatory response does not invalidate the main findings of the study by Wree et al., but requires caution in interpreting them as entirely due to liver intrinsic NLRP3 activation. Certainly the premature death of animals at 2-3 weeks of age may not be due only to liver pathology. Is it possible that the major findings of liver inflammation, hepatocyte pyroptosis, stellate cell activation, and liver fibrosis are due to extrahepatic myeloid cell activation with subsequent accumulation in the liver? This is possible, but due to the significant trafficking of activated immune cells to the liver is very difficult to control for. The stronger phenotype in the total body NLRP3 active Abbreviations: ASH, alcoholic steatohepatitis; DILI, drug-induced liver injury; LPS, lipopolysaccharide; NASH, nonalcoholic steatohepatitis; NLRP3, NLR family pyrin domain containing 3; TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling. Supported by a Veterans Administration Merit Award. Address reprint requests to: W.Z. Mehal, M.D., Ph.D., Section of Digestive Diseases, Yale University, TAC S223A, 1 Gilbert Street, New Haven, CT 06520. E-mail: wajahat.mehal@yale.edu. Copyright VC 2013 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.26674 Potential conflict of interest: Nothing to report.