title: Annexin A2 binds to endosomes and negatively regulates TLR4-triggered inflammatory responses via the TRAM-TRIF pathway.
abstract: Lipopolysaccharide (LPS) derived from Gram-negative bacteria activates plasma membrane signaling via Toll-like receptor 4 (TLR4) on host cells and triggers innate inflammatory responses, but the underlying mechanisms remain to be fully elucidated. Here we reveal a role for annexin A2 (AnxA2) in host defense against infection as anxa2(-/-) mice were highly susceptible to Gram-negative bacteria-induced sepsis with enhanced inflammatory responses. Computing analysis and biochemical experiments identified that constitutive AnxA2 expression facilitated TLR4 internalization and its subsequent translocation into early endosomal membranes. It activated the TRAM-dependent endosomal signaling, leading to the release of anti-inflammatory cytokines. Importantly, AnxA2 deficiency prolonged TLR4-mediated signaling from the plasma membrane, which was attributable to pro-inflammatory cytokine production (IL-6, TNFα and IL-1β). Thus, AnxA2 directly exerted negative regulation of inflammatory responses through TLR4-initiated TRAM-TRIF pathway occurring on endosomes. This study reveals AnxA2 as a critical regulator in infection-initiated inflammation, which protects the host from excessive inflammatory damage.
authors.affiliation: Department of Basic Sciences, University of North Dakota, Grand Forks, North Dakota 58203-9037, USA.|State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Basic Sciences, University of North Dakota, Grand Forks, North Dakota 58203-9037, USA.|Department of thoracic oncology, West China Hospital, Sichuan University, Chengdu 610041, China.
authors.forename: Min
authors.initials: M
authors.lastname: Yu
authors.affiliation: Department of Basic Sciences, University of North Dakota, Grand Forks, North Dakota 58203-9037, USA.|Department of Rheumatology, Renji Hospital, Shanghai Jiaotong University, Shanghai 200127, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Guo
authors.affiliation: Department of Basic Sciences, University of North Dakota, Grand Forks, North Dakota 58203-9037, USA.|College of Biotechnology and Pharmaceutical Engineering, Nanjing University of Technology, Nanjing 211800, China.
authors.forename: Rongpeng
authors.initials: R
authors.lastname: Li
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
authors.forename: Guobo
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Basic Sciences, University of North Dakota, Grand Forks, North Dakota 58203-9037, USA.|Laboratory of Biochemistry and Molecular Biology, School of Life Sciences, Yunnan University, Kunming 650091, China.
authors.forename: Shirui
authors.initials: S
authors.lastname: Tan
authors.affiliation: Department of Basic Sciences, University of North Dakota, Grand Forks, North Dakota 58203-9037, USA.|State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Li
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
authors.forename: Yuquan
authors.initials: Y
authors.lastname: Wei
authors.affiliation: Department of Basic Sciences, University of North Dakota, Grand Forks, North Dakota 58203-9037, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Wu
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D017306:Annexin A2 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D011992:Endosomes / Q000276:immunology* / Q000378:metabolism; D005260:Female; D054884:Host-Pathogen Interactions / Q000276:immunology; D015151:Immunoblotting; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism; D007710:Klebsiella Infections / Q000276:immunology / Q000382:microbiology; D007711:Klebsiella pneumoniae / Q000276:immunology / Q000502:physiology; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D010587:Phagocytosis / Q000276:immunology / Q000502:physiology; D011014:Pneumonia / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D011485:Protein Binding; D034622:RNA Interference; D018123:Receptors, Interleukin / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000276:immunology* / Q000378:metabolism
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D017306:Annexin A2; D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D018123:Receptors, Interleukin; D051197:Toll-Like Receptor 4; C476286:Ticam1 protein, mouse; C476416:Ticam2 protein, mouse; C493487:Tlr4 protein, mouse