Alcohol-induced liver injury is modulated by Nlrp3 and Nlrc4 inflammasomes in mice.
Alcoholic liver disease (ALD) is characterized by increased hepatic lipid accumulation (steatosis) and inflammation with increased expression of proinflammatory cytokines. Two of these cytokines, interleukin-1 β (IL-1 β ) and IL-18, require activation of caspase-1 via members of the NOD-like receptor (NLR) family. These NLRs form an inflammasome that is activated by pathogens and signals released through local tissue injury or death. NLR family pyrin domain containing 3 (Nlrp3) and NLR family CARD domain containing protein 4 (Nlrc4) have been studied minimally for their role in the development of ALD. Using mice with gene targeted deletions for Nlrp3 (Nlrp3(-/-)) and Nlrc4 (Nlrc4(-/-)), we analyzed the response to chronic alcohol consumption. We found that Nlrp3(-/-) mice have more severe liver injury with higher plasma alanine aminotransferase (ALT) levels, increased activation of IL-18, and reduced activation of IL-1B. In contrast, the Nlrc4(-/-) mice had similar alcohol-induced liver injury compared to C57BL/6J (B6) mice but had greatly reduced activation of IL-1 β . This suggests that Nlrp3 and Nlrc4 inflammasomes activate IL-1 β and IL-18 via caspase-1 in a differential manner. We conclude that the Nlrp3 inflammasome is protective during alcohol-induced liver injury.
Departments of Nutrition, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106, USA.
David A
DA
DeSantis
Departments of Nutrition, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106, USA.
Chih-Wei
CW
Ko
Departments of Nutrition, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106, USA.
Yang
Y
Liu
Department of Anatomic Pathology, Cleveland Clinic, Cleveland, OH 4406, USA.
Xiuli
X
Liu
Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA ; Department of Medicine, Louis Stokes Cleveland Department of Veterans' Affairs Medical Center, Cleveland, OH 44106, USA ; Center for Global Health and Diseases, Case Western Reserve University, Cleveland, OH 44106, USA.
Amy G
AG
Hise
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Gabriel
G
Nunez
Departments of Nutrition, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106, USA.
Colleen M
CM
Croniger
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000502:physiology*; D002135:Calcium-Binding Proteins / Q000502:physiology*; D002352:Carrier Proteins / Q000502:physiology*; D018932:Chemokine CCL2 / Q000502:physiology; D002796:Choline Deficiency / Q000150:complications; D058847:Inflammasomes / Q000502:physiology*; D020382:Interleukin-18 / Q000502:physiology; D053583:Interleukin-1beta / Q000502:physiology; D008108:Liver Diseases, Alcoholic / Q000209:etiology*; D008715:Methionine / Q000172:deficiency; D051379:Mice; D008810:Mice, Inbred C57BL; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D050796:STAT3 Transcription Factor / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D051017:Apoptosis Regulatory Proteins; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D058847:Inflammasomes; D020382:Interleukin-18; D053583:Interleukin-1beta; C512299:Ipaf protein, mouse; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D008715:Methionine