The implication of neutrophil extracellular traps in nonalcoholic fatty liver disease - PubMed (original) (raw)

Figure 1

NETs regulate inflammatory response during NAFLD progression. (Steatosis) Myeloid cells with p38γ/δ deficiency are resistant to HFD-induced steatosis. F6 induces NETs formation through activating ERK, JNK, and AKT signaling pathways. However, FFAs induce NETs formation by activating ERK, JNK, but not AKT kinase. IL-17RA-/- mice fed with HFD have experienced decreased intestinal neutrophil migration, indicating gut microbiota may be a potential modulator of NETs formation during NAFLD. (NASH-fibrosis) In the progression of NASH-fibrosis, S1PR2 functions as a catalyst for NETs formation, and silencing S1PR2 can mitigate hepatic fibrosis and inflammation. NETs generation fosters the differentiation of Treg and facilitates the advancement of HCC. NETs entice MDMs, subsequently reshaping the inflammatory milieu within NASH. Neutrophils activate HSC by inducing the production of ROS and MPO. ABX treatment may inhibit NETs formation during liver fibrosis. IL-17 and IL-22 produced by neutrophils promote liver fibrosis development through TGF-β signaling. (Cirrhosis) NETs markers exhibit a marked increase in patients with liver cirrhosis and portal vein thrombosis. During liver cirrhosis, NETs formation assumes a role in promoting coagulation. IL-22 and IL-17 production from neutrophils potentially promote NETs formation through STAT3 signaling during NAFLD. (HCC) Neutrophils expressing CXCR2 infiltrate in the course of NASH-HCC development, and a combined therapy involving PD-1 antibodies and CXCR2 inhibitor (AZD5069) reshapes the behavior of TANs. HCC cells internalize NETs, leading to elevated COX2 levels through activation of TLR4/9. FFA, free fatty acid; F6, furanoid F-acid F6; ERK, extracellular signal-regulated kinase; JNK, c-Jun N-terminal kinase; AKT, protein kinase B; IL-17RA, interleukin-17 (IL-17) receptor; S1PR2, specific G protein-coupled S1P receptor 2; ABX, antibiotics; IL-17, interleukin-17; IL-22, interleukin-22. STAT3, signal transducer and activator of transcription 3; MDMs, monocyte-derived macrophages; TAT, thrombin-antithrombin complex; PVT, portal vein thrombosis; HCC, hepatocellular carcinoma; ROS, reactive oxygen species; MPO, myeloperoxidase; CSF-1, colony stimulating factor 1; XCR1, X-C motif chemokine receptor 1; DC, dendritic cells; PD-1, programmed death protein-1; CXCR2, CXC chemokine receptor 2; TANs, tumor-associated neutrophils; COX2, cyclooxygenase-2; IL-1a/β, interleukin-1a/β.