The NLRP3 Inflammasome and IL-1β Accelerate Immunologically Mediated Pathology in Experimental Viral Fulminant Hepatitis

Abstract

Viral fulminant hepatitis (FH) is a severe disease with high mortality resulting from excessive inflammation in the infected liver. Clinical interventions have been inefficient due to the lack of knowledge for inflammatory pathogenesis in the virus-infected liver. We show that wild-type mice infected with murine hepatitis virus strain-3 (MHV-3), a model for viral FH, manifest with severe disease and high mortality in association with a significant elevation in IL-1β expression in the serum and liver. Whereas, the viral infection in IL-1β receptor-I deficient (IL-1R1 -/-) or IL-1R antagonist (IL-1Ra) treated mice, show reductions in virus replication, disease progress and mortality. IL-1R1 deficiency appears to debilitate the virus-induced fibrinogen-like protein-2 (FGL2) production in macrophages and CD45+Gr-1high neutrophil infiltration in the liver. The quick release of reactive oxygen species (ROS) by the infected macrophages suggests a plausible viral initiation of NLRP3 inflammasome activation. Further experiments show that mice deficient of p47 phox, a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit that controls acute ROS production, present with reductions in NLRP3 inflammasome activation and subsequent IL-1β secretion during viral infection, which appears to be responsible for acquiring resilience to viral FH. Moreover, viral infected animals in deficiencies of NLRP3 and Caspase-1, two essential components of the inflammasome complex, also have reduced IL-1β induction along with ameliorated hepatitis. Our results demonstrate that the ROS/NLRP3/IL-1β axis institutes an essential signaling pathway, which is over activated and directly causes the severe liver disease during viral infection, which sheds light on development of efficient treatments for human viral FH and other severe inflammatory diseases.

Clara Cell 10 kDa Protein Alleviates Murine Hepatitis Virus Strain 3-Induced Fulminant Hepatitis by Inhibiting Fibrinogen-Like Protein 2 Expression

“…Previous studies suggested fgl2 played a vital role in this process with a 15-40% increase of survival when fgl2 was deleted (12,15,27,28). Multiple inflammatory factors or mediators including TNF-α and IFN-γ, IL-1β and C5aR have been demonstrated to promote FH progression with significant discrepancies between liver damage and survival rate (29)(30)(31)(32), which is accordant with our observation that CC10 substantially alleviated liver injury though survival rate improved mildly. The survival rate based on hours may be more accurate to examine the effect of CC10 on FH.…”

The anti-viral facet of anti-rheumatic drugs: Lessons from COVID-19

“…Blocking of IL-17A or IL-1 resulted to be potential targets for therapeutic treatment of viral exacerbations of chronic lung inflammation [219]. Authors described that inflammasome complex/IL-1β are an essential signaling pathway, which is over activated and directly causes the severe liver disease during viral infection [220]. Anakinra (ANK), a human IL-1R antagonist, has been approved for the treatment of RA, AOSD, and other severe autoimmune and autoinflammatory disorders including tumor necrosis factor receptor-associated periodic syndrome (TRAPS) [221].…”

Inflammasomes and their roles in the pathogenesis of viral hepatitis and their related complications: An updated systematic review

“…Inflammasomes are also the molecules responsible for induction of inflammation in the liver following injection of alum [53]. NLRP3 inflammasome and its signaling molecules also significantly participate in the induction of fulminant hepatitis by MHV [54]. However, studies regarding HCV and HBV revealed the induction of chronic hepatitis by inflammasomes and their related molecules, including ASC, caspase-1, IL-1β, and IL-18 [55][56][57].…”