PMID- 35489123 OWN - NLM STAT- MEDLINE DCOM- 20220527 LR - 20220527 IS - 1618-0631 (Electronic) IS - 0344-0338 (Linking) VI - 234 DP - 2022 Jun TI - Notch1 signaling contributes to TLR4-triggered NF-kappaB activation in macrophages. PG - 153894 LID - S0344-0338(22)00138-8 [pii] LID - 10.1016/j.prp.2022.153894 [doi] AB - Macrophages substantially influence the development, progression, and complications of inflammation-driven diseases. Although numerous studies support the critical role of Notch signaling in most inflammatory diseases, there is limited data on the role of Notch signaling in TLR4-induced macrophage activation and interaction of Notch signaling with other signaling pathways in macrophages during inflammation, such as the NF-kappaB pathway. This study confirmed that stimulation with lipopolysaccharide (LPS), a TLR4 ligand, upregulated Notch1 expression in monocyte/macrophage-like RAW264.7 cells and bone marrow-derived macrophages (BMDMs). LPS also induced increased mRNA expression of Notch target genes Notch1 and Hes1 in macrophages, suggesting that TLR4 signaling enhances activation of the Notch pathway. The upregulation of Notch1, Notch1 intracellular domain (NICD), and Hes1 proteins by LPS treatment was inhibited by DAPT, a Notch1 inhibitor. Additionally, the increased TNF-alpha, IL-6, and IL-1beta expression induced by LPS was inhibited by DAPT and rescued by jagged1, a Notch1 ligand. Furthermore, suppression of Notch signaling by DAPT upregulated Cylindromatosis (CYLD) expression but downregulated TRAF6 expression, IkappaB kinase (IKK) alpha/beta phosphorylation, and subsequently, phosphorylation and degradation of IkappaB-alpha, indicating that DAPT inhibited NF-kappaB activation triggered by TLR-4. Interestingly, DAPT did not inhibit the increased MyD88 expression induced by LPS. Our study findings demonstrate that macrophage stimulation via the TLR4 signaling cascade triggers activation of Notch1 signaling, which regulates the expression patterns of genes involved in pro-inflammatory responses by activating NF-kappaB. This effect may be dependent on the CYLD-TRAF6-IKK pathway. Thus, Notch1 signaling may provide a therapeutic target against infectious and inflammation-driven diseases. CI - Copyright (c) 2022 Elsevier GmbH. All rights reserved. FAU - Li, Li AU - Li L AD - Jilin Key Laboratory for Immune and Targeting Research on Common Allergic Diseases, Yanbian University, Yanji 133002, PR China; Department of Anatomy, Histology and Embryology, Yanbian University Medical College, Yanji 133002, PR China. FAU - Jin, Jin-Hua AU - Jin JH AD - Department of Anesthesiology, Plastic Surgery Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Ba-Da-Chu Road,Shi-Jing-Shan District, Bejing 100144, PR China. FAU - Liu, Han-Ye AU - Liu HY AD - Jilin Key Laboratory for Immune and Targeting Research on Common Allergic Diseases, Yanbian University, Yanji 133002, PR China; Department of Anatomy, Histology and Embryology, Yanbian University Medical College, Yanji 133002, PR China. FAU - Ma, Xiao-Fei AU - Ma XF AD - Jilin Key Laboratory for Immune and Targeting Research on Common Allergic Diseases, Yanbian University, Yanji 133002, PR China; Department of Anatomy, Histology and Embryology, Yanbian University Medical College, Yanji 133002, PR China. FAU - Wang, Dan-Dan AU - Wang DD AD - Jilin Key Laboratory for Immune and Targeting Research on Common Allergic Diseases, Yanbian University, Yanji 133002, PR China; Department of Anatomy, Histology and Embryology, Yanbian University Medical College, Yanji 133002, PR China. FAU - Song, Yi-Lan AU - Song YL AD - Jilin Key Laboratory for Immune and Targeting Research on Common Allergic Diseases, Yanbian University, Yanji 133002, PR China; Department of Anatomy, Histology and Embryology, Yanbian University Medical College, Yanji 133002, PR China. FAU - Wang, Chong-Yang AU - Wang CY AD - Jilin Key Laboratory for Immune and Targeting Research on Common Allergic Diseases, Yanbian University, Yanji 133002, PR China; Department of Anatomy, Histology and Embryology, Yanbian University Medical College, Yanji 133002, PR China. FAU - Jiang, Jing-Zhi AU - Jiang JZ AD - Jilin Key Laboratory for Immune and Targeting Research on Common Allergic Diseases, Yanbian University, Yanji 133002, PR China; Department of Anatomy, Histology and Embryology, Yanbian University Medical College, Yanji 133002, PR China. FAU - Yan, Guang-Hai AU - Yan GH AD - Jilin Key Laboratory for Immune and Targeting Research on Common Allergic Diseases, Yanbian University, Yanji 133002, PR China; Department of Anatomy, Histology and Embryology, Yanbian University Medical College, Yanji 133002, PR China. FAU - Qin, Xiang-Zheng AU - Qin XZ AD - Department of Anatomy, Histology and Embryology, Yanbian University Medical College, Yanji 133002, PR China. Electronic address: qinxzh@ybu.edu.cn. FAU - Li, Liang-Chang AU - Li LC AD - Jilin Key Laboratory for Immune and Targeting Research on Common Allergic Diseases, Yanbian University, Yanji 133002, PR China; Department of Anatomy, Histology and Embryology, Yanbian University Medical College, Yanji 133002, PR China. Electronic address: lclee@ybu.edu.cn. LA - eng PT - Journal Article DEP - 20220413 PL - Germany TA - Pathol Res Pract JT - Pathology, research and practice JID - 7806109 RN - 0 (Ligands) RN - 0 (Lipopolysaccharides) RN - 0 (NF-kappa B) RN - 0 (NOTCH1 protein, human) RN - 0 (Platelet Aggregation Inhibitors) RN - 0 (Receptor, Notch1) RN - 0 (TLR4 protein, human) RN - 0 (TNF Receptor-Associated Factor 6) RN - 0 (Toll-Like Receptor 4) RN - EC 2.7.11.10 (I-kappa B Kinase) SB - IM MH - Humans MH - I-kappa B Kinase/metabolism MH - Inflammation/metabolism MH - Ligands MH - Lipopolysaccharides/pharmacology MH - Macrophages/metabolism MH - *NF-kappa B/metabolism MH - Platelet Aggregation Inhibitors/metabolism/pharmacology MH - Receptor, Notch1/metabolism MH - TNF Receptor-Associated Factor 6/metabolism/pharmacology MH - *Toll-Like Receptor 4/genetics OTO - NOTNLM OT - Macrophage OT - NF-kappaB OT - Notch1 OT - TLR4 EDAT- 2022/05/01 06:00 MHDA- 2022/05/28 06:00 CRDT- 2022/04/30 18:13 PHST- 2021/12/24 00:00 [received] PHST- 2022/03/29 00:00 [revised] PHST- 2022/04/08 00:00 [accepted] PHST- 2022/05/01 06:00 [pubmed] PHST- 2022/05/28 06:00 [medline] PHST- 2022/04/30 18:13 [entrez] AID - S0344-0338(22)00138-8 [pii] AID - 10.1016/j.prp.2022.153894 [doi] PST - ppublish SO - Pathol Res Pract. 2022 Jun;234:153894. doi: 10.1016/j.prp.2022.153894. Epub 2022 Apr 13.