FIGURE 2.

Immune regulation in liver fibrosis. (A) Inflammation is a major process in the development of fibrosis. MtDAMPs, including mtDNA, N-formyl peptides, and ATP, are released to extracellular space in the case of ROS-driven mitochondrial membrane permeability transition. MtDNA can activate NLRP3 inflammasomes, TLR9, and cGAS-STING, which separately induce HSCs, neutrophil, and KCs activation. NFPs are released from dysfunctional mitochondrial, binding to FPRs, which leads to the migration of neutrophil cells to the injury tissue. Released ATP binds to P2X7 receptors on neutrophils, inducing NLRP3-ASC-caspase-1 inflammasome and IL-1β secretion. (B) MSCs act as a bridge to prevent inflammation and oxidative stress via extracellular vesicles, etc. MSCs suppress the proliferation of Th17 cells and decrease the expression of IL-17A and il-17RA. Meanwhile, MSCs promote the activation of M2 macrophages and inhibit M1 macrophages activation, hypoxia-preconditioning, and HIF-1 overexpression can improve MSC therapeutic. (C) HIF may play different roles in different cells. The chronic liver injury activates HIF-1α in macrophages, which may regulate the expression of PDGF-B to induce HSCs activation and fibrosis. However, liver necrotic cells can also activate HIF-1α in HSCs. HIF-1α then stimulated recruited macrophages to remove necrotic hepatocytes and alleviate fibrosis.