title: Notch-Hes-1 axis controls TLR7-mediated autophagic death of macrophage via induction of P62 in mice with lupus.
abstract: The increased death of macrophages has been considered as a pathogenic factor for systemic lupus erythematosus (SLE), and dysfunction of autophagy may contribute to improper cell death. However, the effect of autophagy on macrophage during the pathogenesis of SLE is still unclear. Here we found that the death rate and autophagy level of macrophages significantly increased in MRL/lpr lupus-prone mice. Activation of toll-like receptor 7 (TLR7) triggered macrophage death in an autophagy-dependent but caspase-independent way in vitro. Moreover, P62/SQSTM1 is thought to have an essential role in selective autophagy. We also demonstrated that P62/SQSTM1 was required for TLR7-induced autophagy, and knockdown of P62 suppressed R848-induced cell death and LC3II protein accumulation. As an important mediator for cell-cell communication, Notch signaling is responsible for cell-fate decisions. Our results showed that activation of TLR7 also upregulated the expression of Notch1, especially its downstream target gene Hairy and enhancer of split 1 (Hes-1) in macrophages. Of note, we found that Hes-1, as a transcriptional factor, controlled TLR7-induced autophagy by regulating P62 expression. Furthermore, to confirm the above results in vivo, TLR7 agonist imiquimod (IMQ)-induced lupus mouse model was prepared. Splenic macrophages from IMQ-treated mice exhibited increased autophagy and cell death as well as enhanced expressions of Notch1 and Hes-1. Our results indicate that Notch1-Hes-1 signaling controls TLR7-induced autophagic death of macrophage via regulation of P62 in mice with lupus.
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing 210093, China.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Li
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing 210093, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Liu
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing 210093, China.
authors.forename: Xuefang
authors.initials: X
authors.lastname: Zhang
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing 210093, China.
authors.forename: Guoping
authors.initials: G
authors.lastname: Shi
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing 210093, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Ren
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing 210093, China.
authors.forename: Jianjian
authors.initials: J
authors.lastname: Ji
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing 210093, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Ding
authors.affiliation: State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Hongye
authors.initials: H
authors.lastname: Fan
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing 210093, China.|Jiangsu Key Laboratory of Molecular Medicine, Nanjing 210093, China.
authors.forename: Huan
authors.initials: H
authors.lastname: Dou
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing 210093, China.|Jiangsu Key Laboratory of Molecular Medicine, Nanjing 210093, China.
authors.forename: Yayi
authors.initials: Y
authors.lastname: Hou
mesh_terms: D000818:Animals; D001343:Autophagy; D004195:Disease Models, Animal; D005260:Female; D008180:Lupus Erythematosus, Systemic / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D000067996:RAW 264.7 Cells; D051880:Receptors, Notch / Q000378:metabolism*; D000071456:Sequestosome-1 Protein / Q000378:metabolism*; D015398:Signal Transduction; D051199:Toll-Like Receptor 7 / Q000378:metabolism*; D000072056:Transcription Factor HES-1 / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C489734:Hes1 protein, mouse; D051880:Receptors, Notch; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; D051199:Toll-Like Receptor 7; D000072056:Transcription Factor HES-1