engleski

Hepatic inflammation and disease severity during Hepatitis C virus infection is linked with macrophage IL-1β production through the NLRP3 inflammasome

Hepatitis C virus (HCV) mediates chronic infection, but the molecular mechanisms of hepatic inflammation during infection are not well defined. IL-1β is a pleiotropic cytokine that serves to recruit immune cells to the site of infection, modulate immune cell effector function and mediate tissue pathology. This key proinflammatory cytokine is the product of the inflammasome signaling pathway that requires a first signal to stimulate NFKB activation and trigger IL-1β expression and a second signal to induce a Nod-Like receptor (NLR) activation to activate downstream caspase-1, which processes proIL-1β into bioactive secreted cytokine. Here, we show that patients with chronic HCV produce higher levels of IL-1β compared to healthy controls. Furthermore, global transcriptome analysis by RNA-seq revealed that IL-1β expression generally associated with HCV infection and the onset of liver disease, with high levels of IL-1β and IL-1β- responsive proinflammatory cytokines and chemokines present in HCV cirrhotic liver. We also performed immunohistochemical staining on healthy and chronic HCV liver using anti-CD68 to mark macrophages, including Kupffer cells, the liver-resident myeloid cells, and identified that macrophages are the major producers of hepatic IL-1β in chronic HCV. Using differentiated THP-1 as an in vitro model of HCV exposu- re to macrophages, we found that phagocytic mediated uptake of HCV is critical to induce IL-1β production. In addition, HCV triggers NLRP3 inflammasome activation through potassium efflux to produce mature IL-1β from macrophages. We also found that the polyU/UC region within the 3’UTR of viral RNA genome is sufficient to trigger IL-1β mRNA expression through TLR7/MyD88 signaling. We conclude that HCV uptake by macrophages or Kupffer cells triggers the production of IL-1β and proinflammatory response, which mediates hepatic inflammation and promote liver disease during HCV infection.

HCV; inflammation; Kupffer cells; IL1; inflammasome

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