Roles of heterogenous liver macrophages during the progression of liver injury. Under the pathologic process of liver injury, the resident embryonic-derived Kupffer cells (EmKCs) located inside the sinusoidal endothelium recognize microbial pathogen-associated molecular patterns (PAMPs) and damaged cell-released damage-associated molecular pattern (DAMPs) via PRRs and inflammasome. The activated EmKCs release inflammatory cytokines and CCL2 chemokine to recruit circulating monocytes. They develop into inflammatory Ly6Cpos monocyte-derived macrophages (MoMFs) or anti-inflammatory Ly6Cneg MoMFs to promote or suppress fibrotic activation of hepatic stellate cells (HSCs). MoMFs can fully differentiate toward monocyte-derived KCs (MoKCs) by activation of LXRα and ID3 transcription factors. TREM2 and CD9 positive lipid-associated macrophages (LAMs) are derived from MoKCs and their roles in the development of liver injury has not been identified yet. The stimulation, differentiation, and conversion of hepatic macrophages are indicated as shown colored arrows.
