Hepatitis C virus activates interleukin-1β via caspase-1-inflammasome complex

Abstract

Interleukin-1b (IL-1b) is a potent pro-inflammatory cytokine involved in the pathogenesis of HCV, but the sensors and underlying mechanisms that facilitate HCV-induced IL-1b proteolytic activation and secretion remains unclear. In this study, we have identified a signalling pathway leading to IL-1b activation and secretion in response to HCV infection. Previous studies have shown the induction and secretion of IL-1b through the inflammasome complex in macrophages/monocytes. Here, we report for the first time the induction and assembly of the NALP3-inflammasome complex in human hepatoma cells infected with HCV (JFH-1). We demonstrate that activation of IL-1b in HCVinfected cells involves the proteolytic processing of pro-caspase-1 into mature caspase-1 in a multiprotein inflammasome complex. Next, we demonstrate that HCV is sensed by NALP3 protein, which recruits the adaptor protein ASC for the assembly of the inflammasome complex. Using a small interfering RNA approach, we further show that components of the inflammasome complex are involved in the activation of IL-1b in HCV-infected cells. Our study also demonstrates the role of reactive oxygen species in HCV-induced IL-1b secretion. Collectively, these observations provide an insight into the mechanism of IL-1b processing and secretion, which is likely to provide novel strategies for targeting the viral or cellular determinants to arrest the progression of liver disease associated with chronic HCV infection.

Platelets mediate increased endothelium permeability in dengue through NLRP3-inflammasome activation

“…16 Assembly of NLRP3 inflammasomes has also been described in other viral infections, including those by the DV family flavivirus. 37,38 When hepatitis C virus infects hepatocytes, it induces the assembly of NLRP3-ASC-caspase-1 complex and, as a consequence, increases IL-1b secretion. 37 Here, we observed evidence for ASC recruitment by NLRP3 leading to caspase-1 activation in platelets from DV-infected patients, providing new evidence for DV-induced inflammasome activation and its occurrence in this critical effector cell.…”

“…37,38 When hepatitis C virus infects hepatocytes, it induces the assembly of NLRP3-ASC-caspase-1 complex and, as a consequence, increases IL-1b secretion. 37 Here, we observed evidence for ASC recruitment by NLRP3 leading to caspase-1 activation in platelets from DV-infected patients, providing new evidence for DV-induced inflammasome activation and its occurrence in this critical effector cell. Also, our studies indicate that activation of the caspase-1 inflammasome mediates shedding of IL-1b-containing MPs by platelets.…”

Kupffer cell in the immune activation and tolerance toward HBV/HCV infection

“…In patients infected with HCV, the level of IL-1β and caspase-1 in KCs decreases significantly after they are treated with pyrrolidineditiocarbamate and/or bafilomycin A. 48 The increase in the NLRP3 inflammasome mRNA in the livers of chronic HBV patients illustrates the up-regulation of NLRP3 expression in KCs, which has been proven by immunohistochemistry. 49 As a result, HBV/HCV tolerance might be induced by blocking IL-1β through suppression of the NLRP3 inflammasome in KCs.…”

Caspase-12 and Lupus: The Curious Case of the Dog That Didn’t Bark

“…CASP12's effects upon TNF production, which is elevated in all lupus patients, especially African-Americans [30] , is also contradictory [5,28,31] . Further, while hepatitis C virus is an IL-1β inducer [32] , CASP12 genotype has no effect on the clearance of this pathogen [33] . Confounding the metabolic findings described above by Skeldon and co-workers, no protective effects are found in African-American adults with CASP12 when metabolic parameters or C-reactive protein levels were assessed.…”