Mononuclear phagocyte system in hepatitis C virus infection

Figure 2 Role of macrophages in hepatitis C virus infection-associated inflammation. During hepatitis C virus (HCV) infection, macrophages are the main source of the proinflammatory cytokines [interleukin (IL)-1β, IL-18, tumor necrosis factor (TNF)-α, and IL-6] and the anti-inflammatory IL-10. The production of IL-1β and IL-18 requires two signals, which are initiated by the uptake of intact HCV particles. Signal 1: Following dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin-mediated endocytosis, the HCV genome is released into cytoplasm and the uridine-rich HCV RNA is recognized by endosomal Toll-like receptor 7 (TLR7). This recognition leads to pro-IL-1β and IL-18 production in a myeloid differentiation primary response gene 88 and nuclear factor-κB (NFκB)-dependent manner. Signal 2: Pro IL-1β and IL-18 become activated in this pathway. HCV p7, an ion channel protein, promotes potassium efflux that activates the nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome. Utilizing apoptosis-associated speck-like protein containing a CARD as an adaptor protein, NLRP3 activates caspase-1, which induces the maturation of pro-IL-1β and pro-IL-18 into their active forms. HCV core and NS3 proteins interact with TLR1 or TLR6 and TLR2 to activate NFκB, which results in the production of TNF-α, IL-6, and IL-10. Additionally, HCV particles can also be recognized by TLR7/8, inducing TNF-α production. TLR tolerance is a protection mechanism against uncontrolled inflammation. In HCV infection, it can be abrogated by interferon-γ through NF-κB signaling, leading to the production of high levels of proinflammatory cytokines. HCV: Hepatitis C virus; HCVc: HCV core protein; IL: Interleukin; TLR: Toll-like receptor; TNF-α: Tumor necrosis factor α; DC-SIGN: Dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin; TLR: Toll-like receptor; MYD88: Myeloid differentiation primary response gene 88; NF-κB: Nuclear factor-κB; NLRP3: Nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3; ASC: Apoptosis-associated speck-like protein containing a CARD; NS3: Nonstructural protein 3; IFN-γ: Interferon-γ.