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

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The NLRP3 inflammasome and IL-1β play essential roles in mediating the primary inflammatory responses against pathogen invasions in the host. Hyperactivation of this signaling pathway can lead to life-threatening diseases under certain circumstances. However, it is not clear if NLRP3 inflammasome activation participates in the pathogenesis of viral fulminant hepatitis (FH), a clinical severe syndrome characterized by acute inflammation in the liver along with massive necrosis of hepatocytes and hepatic encephalopathy during viral infection. Using a mouse viral FH model by infection with murine hepatitis virus strain-3 (MHV-3), we observed a significant macrophage induction and the serum and liver massive accumulation of IL-1β. Conversely, interruption of IL-1β signals results in attenuation of the MHV-3-induced hepatitis and mortality. Blocking IL-1β activity reduces the virus-induced expression of fibrinogen-like protein-2 (FGL2) in macrophages, and limits the liver recruitment of CD45+Gr-1high neutrophils upon the virus infection. We further show that proIL-1β is bioprocessed by NLRP3 inflammasome. Deletion of the components in the inflammasome complex, including NLRP3 and Caspase-1, leads to reduction in the virus-induced IL-1β production and lessening of disease progression. Further studies show that macrophages in deficiency of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit p47phox, a protein that controls acute ROS production, prevents NLRP3 inflammasome activation and IL-1β secretion, suggesting that the virus-induced ROS production can directly initiate NLRP3 inflammasome activation. Therefore, p47phox-/- mice exhibited certain degrees of MHV-3 resistance. Taken together, these results demonstrate that ROS/NLRP3/IL-1β is the key pathway signaling exacerbated inflammatory responses that cause viral FH in mice, suggesting that mediation of this signal cascade may benefit on the disease treatment.

Vyšlo v časopise: The NLRP3 Inflammasome and IL-1β Accelerate Immunologically Mediated Pathology in Experimental Viral Fulminant Hepatitis. PLoS Pathog 11(9): e32767. doi:10.1371/journal.ppat.1005155
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1005155

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