Targeting NFKB by autophagy to polarize hepatoma-associated macrophage differentiation.
Tumor-associated macrophages (TAMs) have been linked to promoting tumor progression by stimulating angiogenesis, cell growth and inflammation. NFKB activity in TAMs may mediate inflammation-associated tumor formation. However, most isolated TAMs from established tumors express a M2 phenotype with less NFKB activation and show a strong immunosuppressive phenomenon. How tumors affect the dynamic of NFKB activity in TAMs, and hence maintain their pro-tumor M2 phenotype is still poorly understood. We recently found that hepatoma-derived toll-like receptor 2 (TLR2)-related ligands are capable of stimulating M2 macrophage differentiation via controlling NFKB RELA/p65 protein homeostasis by selective autophagy. TLR2 signal induces NFKB RELA cytosolic ubiquitination and leads to its degradation by SQSTM1/p62-mediated autophagy. Inhibition of autophagy will rescue NFKB activity and shape the phenotype of hepatoma-polarized M2 macrophages. This suggests that autophagy might play a role in manipulating TAM functions and tumor-associated immune responses. Our study also demonstrates that autophagy can directly control a transcriptional factor in addition to its regulatory molecules. This finding uncovers a new role of autophagy in controlling cellular functions.
Department of Microbiology & Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan. cpchang@mail.ncku.edu.tw
Chih-Peng
CP
Chang
Yu-Chi
YC
Su
Pei-Huan
PH
Lee
Huan-Yao
HY
Lei
D000818:Animals; D001343:Autophagy; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D002454:Cell Differentiation; D016764:Cell Polarity; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology*; D008264:Macrophages / Q000473:pathology*; D051379:Mice; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism*; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000378:metabolism
D016328:NF-kappa B; D051195:Toll-Like Receptor 2
NFKB; SQSTM1/p62; TLR2; selective autophagy; tumor-associated macrophages