NLRP3 Inflammasome and IL-33: Novel Players in Sterile Liver Inflammation
Abstract
:1. Introduction
2. Sterile Inflammation-Associated Liver Diseases
2.1. Nonalcoholic Fatty Liver Disease
2.2. Alcoholic Liver Disease
2.3. Drug-Induced Liver Injury
2.4. Liver Ischemia/Reperfusion (I/R) Injury
2.5. Autoimmune Hepatitis (AIH)
3. The Inflammasome
3.1. Inflammasome Function
3.2. Inflammasome Activation
3.3. IL-1β and NLRP3 Inflammasome
4. NLRP3 Inflammasome Activation in Sterile Inflammation-Associated Liver Diseases
4.1. NAFLD
4.2. ALD
4.3. Drug-Induced Liver Injury
4.4. Liver I/R
4.5. AIH
5. The Alarmin IL-33
5.1. Molecular Biology
5.2. The IL-33 Receptor ST2
5.3. IL-33 Expression and Immune Cell Regulation
5.4. IL-33 in Inflammatory Diseases
6. IL-33/ST2 Axis in Sterile Inflammation-Associated Liver Diseases
6.1. NAFLD
6.2. ALD
6.3. Drug-Induced Liver Injury
6.4. Liver I/R
6.5. AIH
7. NLRP3 Inflammasome and IL-33 in Sterile Inflammation-Associated Liver Diseases
8. Conclusions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
NASH | nonalcoholic steatohepatitis |
I/R | ischemia reperfusion |
AIH | autoimmune hepatitis |
DAMPs | damage-associated molecular patterns |
IL | interleukin |
NAFLD | nonalcoholic fatty liver |
ALD | alcoholic liver disease |
LPS | lipopolysaccharide |
APAP | acetaminophen |
ROS | reactive oxygen species |
Treg | regulatory T cells |
PAMPs | pathogen-associated molecular pattern |
TLR | Toll-like receptor |
TNFα | tumor necrosis factor α |
ATP | adenosine triphosphate |
HMGB1 | high mobility group box 1 |
NLR | nucleotide-binding oligomerization domain-like receptor |
IL-1R | IL-1 receptor |
HSC | hepatic stellate cells |
TXNIP | transcription factor X-box-binding protein |
ConA | Concanavalin A |
ST2 | suppression of tumorigenicity 2 |
ILC2 | type 2 innate lymphoid cells |
AREG | amphiregulin |
IBD | inflammatory bowel disease |
NET | neutrophil extracellular traps |
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Disease | Inflammasome Components | References |
---|---|---|
NAFLD | Elevated NLRP3 and IL-1β levels correlated with liver fibrosis in NASH patients and were increased in different murine models of diet-induced steatohepatitis | [62,63,64,65,66] |
Nlrp3−/− mice showed marked protection from diet-induced liver injury whereas disease pathology was accelerated in Nlrp3 knock-in mice | [62,64,67] | |
Caspase-1 activation in Kupffer cells triggered progression of diet-induced steatohepatitis | [68,69] | |
Extracellular ATP activated the NLRP3 inflammasome in diet-induced steatohepatitis and P2rx7−/− mice showed reduced liver fibrosis | [70] | |
Cholesterol crystals were found in steatotic hepatocytes of patients and mice with NASH, which induced NLRP3 and caspase-1 activation in Kupffer cells | [48,71,72] | |
ALD | Elevated serum IL-1β levels were shown in patients with ALD | [73,74] |
NLRP3/caspase-1-mediated IL-1β production by Kupffer cells aggravated murine ALD | [47] | |
Kupffer cell-derived IL-1β activated invariant NKT cells, which in turn promoted alcohol-induced liver injury by recruiting neutrophils | [75] | |
Extracellular ATP and uric acid were released from alcohol-damaged hepatocytes and stimulated IL-1β production in liver immune cells | [76,77] | |
The miRNA miR-148a inhibited NLRP3 inflammasome activation in alcohol-fed mice and levels of hepatic miR-148a were reduced in patients and mice with ALD | [78] | |
Drug-Induced Liver Injury | Extracellular ATP induced IL-1β production in Kupffer cells and aggravated murine APAP-induced liver injury | [79] |
The P2rx7 antagonist A438079 and soluble CD39 reduced APAP-induced necrosis | [79] | |
Free DNA was released by apoptotic hepatocytes, which induced NLRP3 inflammasome activation in LSEC and neutrophil recruitment in APAP-induced liver injury | [80] | |
Lack of P2rx7, IL-1R and treatment with IL-1β or the pan-caspase inhibitor Z-VD-fmk did not alter pathology of APAP-induced liver injury | [81,82] | |
Liver I/R | Elevated NLRP3 and IL-1β levels were shown in liver I/R injury in a variety of studies and Nlrp3−/− and Casp-1−/− mice showed improved disease pathology | [83,84,85,86,87,88] |
ROS activated the NLRP3 inflammasome in Kupffer cells in liver I/R injury by promoting association of TXNIP with NLRP3 | [83,89] | |
Extracellular histones activated the NLRP3 inflammasome in Kupffer cells in liver I/R injury through generation of ROS leading to recruitment of neutrophils and monocytes | [84] | |
HMGB1 triggered hepatic I/R injury by activation of the NLRP3 inflammasome | [85] | |
HSF1 regulated NLRP3 inflammasome activation in liver I/R injury by suppressing expression of XBP1, an activator of the NLRP3 inflammasome | [90] | |
AIH | Elevated IL-1β levels in patients with AIH were correlated with aggravation of hepatitis | [31] |
Elevated levels of NLRP3, IL-1β, caspase-1, ROS production and pyroptosis-mediated cell death were shown in murine ConA-induced hepatitis | [91,92,93,94] | |
ConA induced NLRP3 inflammasome activation and IL-1β production in macrophages | [94] | |
An IL-1R antagonist suppressed ConA-induced hepatitis by diminishing ROS production and NLRP3 inflammasome activation | [93] | |
The miRNA miR-223 negatively regulated NLRP3 expression and attenuated liver injury in an experimental AIH model | [95] |
Disease | Therapeutic Strategy | References |
---|---|---|
NAFLD | The cholesterol-lowering drug ezetimibe reduced cholesterol crystal formation and fibrosis in murine diet-induced steatohepatitis | [96] |
The small molecule NLRP3 inhibitor MCC950 inhibited Kupffer cell activation and attenuated inflammation and fibrosis in murine diet-induced steatohepatitis | [48,72] | |
ALD | Inhibition of uric acid synthesis with allopurinol and treatment with probenecid, which depletes uric acid and blocks ATP-induced P2rx7 signaling, improved pathology of murine alcohol-induced liver injury | [77] |
The hepatoprotective substance Gentiopicroside inhibited P2rx7-mediated NLRP3 inflammasome activation and ameliorated pathology of murine ALD | [97] | |
Drug-Induced Liver Injury | The P2rx7 antagonist A438079 or soluble CD39 inhibited extracellular ATP signaling and reduced murine APAP-induced liver injury and mortality | [79] |
Aspirin and benzyl alcohol were protective in APAP-induced pathology probably by inhibiting the NLRP3 inflammasome activation and neutrophil infiltration | [80,98] | |
Liver I/R | The ROS inhibitor N-acetylcysteine inhibited NLRP3 inflammasome activation and attenuated murine liver I/R injury | [83] |
Blockage of IL-1β signaling by an anti-IL-1β antibody improved disease pathology of murine liver I/R injury | [85] | |
AIH | An IL-1R antagonist diminished ROS production and NLRP3 inflammasome activation and suppressed liver inflammation in murine ConA-induced hepatitis | [93] |
Disease | Role of IL-33/ST2 | References |
---|---|---|
NAFLD | Serum IL-33 and ST2 levels were elevated in patients with NASH and mice with diet-induced steatohepatitis | [170,171,172] |
Il33−/− mice showed no altered pathology of diet-induced steatohepatitis | [172] | |
IL-33 treatment attenuated steatosis but aggravated fibrosis in diet-induced steatohepatitis | [170] | |
Galectin-3 regulated IL-33-induced expression of the pro-fibrotic cytokine IL-13 in hepatic macrophages in diet-induced steatohepatitis | [173] | |
ALD | Serum IL-33 and sST2 levels were elevated in patients with severe decompensated ALD but not in patients with compensated ALD and heavy drinkers | [174] |
Serum levels of IL-33 were not elevated in alcohol-fed mice and lack of IL-33 did not affect pathogenesis of alcohol-induced liver injury | [174] | |
Hepatic IL-33 expression was increased in murine alcohol-induced liver injury | [47] | |
Drug-Induced Liver Injury | Hepatocytes released IL-33 that induced neutrophil infiltration in murine APAP-induced liver injury | [175] |
Il1rl1−/− mice developed initial liver damage but were protected against progression to extensive necrosis in APAP-induced liver | [175] | |
Liver I/R | LSEC released IL-33 in murine hepatic I/R injury that induced formation of NETs by neutrophils, which promoted hepatocyte death and Kupffer cell activation | [176] |
IL-33 treatment after liver I/R increased NET formation and liver injury | [176] | |
IL-33 treatment before liver I/R reduced hepatocyte death by induction of Bcl-2 | [177] | |
sST2-Fc attenuated hepatic I/R injury by inhibiting Kupffer cell activation | [178] | |
AIH | Elevated serum IL-33 levels correlated with liver injury in AIH patients and both IL-33 and sST2 levels were decreased after immunosuppression therapy | [179] |
NKT cells induced IL-33 expression in hepatocytes in murine ConA-induced hepatitis | [180] | |
TRAIL regulated IL-33 expression in hepatocytes during ConA-induced hepatitis | [181] | |
IL-33 aggravated ConA-induced liver injury by activation of hepatic ILC2 | [182] | |
Blockage of IL-33 attenuated liver injury in two experimental models of AIH | [179,183] | |
Il1rl1−/− mice showed aggravated ConA-induced liver injury and reduced Treg numbers | [184] | |
Il33−/− mice showed exaggerated pathology of ConA-induced hepatitis, increased NK cell infiltration and reduced frequency of ST2+ Tregs | [181,185] | |
IL-33 pre-treatment expanded hepatic ST2+ Tregs and suppressed ConA-induced hepatitis | [182,184] | |
IL-33 treatment together with ConA challenge aggravated ConA-induced hepatitis | [183] |
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Neumann, K.; Schiller, B.; Tiegs, G. NLRP3 Inflammasome and IL-33: Novel Players in Sterile Liver Inflammation. Int. J. Mol. Sci. 2018, 19, 2732. https://doi.org/10.3390/ijms19092732
Neumann K, Schiller B, Tiegs G. NLRP3 Inflammasome and IL-33: Novel Players in Sterile Liver Inflammation. International Journal of Molecular Sciences. 2018; 19(9):2732. https://doi.org/10.3390/ijms19092732
Chicago/Turabian StyleNeumann, Katrin, Birgit Schiller, and Gisa Tiegs. 2018. "NLRP3 Inflammasome and IL-33: Novel Players in Sterile Liver Inflammation" International Journal of Molecular Sciences 19, no. 9: 2732. https://doi.org/10.3390/ijms19092732