title: TRAM1 Promotes Microglia M1 Polarization.
abstract: Microglia, the major immune cells of the central nervous system (CNS), can be driven to adopt M1 and M2 phenotypes. Recently, the distinct functions of M1 and M2 microglia have been intensively studied. M1-activation microglia are pro-inflammatory and may contribute to the development of several CSN disorders, while M2-activation microglia are anti-inflammatory and may promote tissue reconstruction. TRAM1 is a protein involved in translocation of nascent polypeptides and functions as a sorting adaptor of TLR4. Here, we found that TRAM1 plays an important role in microglia M1 polarization. Our results showed that the expression of TRAM1 is highly induced in LPS/interferon (IFN)-γ-stimulated BV2 cells and primary microglia cells. Flag-TRAM1 transfection, but not Flag-GFP used as a control, significantly enhanced M1 polarization by strongly increasing expression of M1 makers, such as IL-6, IL-1β, iNOS, and so on. Silence of TRAM1 effectively inhibited LPS/IFN-γ-induced expression of M1-related genes in BV2 cells. In addition, TRAM1 was found to cooperate with TLR4 to induce an M1 genetic program in Flag-TRAM1-transfected and LPS/IFN-γ-induced BV2 cells. TRAM1 is essential for LPS/IFN-γ induced expressions of adapter molecule (IRAK1, phosphorylation of TBK1, and IRF3) of TLR4. TRAM1 is also essential for phosphorylation of IκB and P65 and for P65-NF-kB translocation to nucleus. Overall, our findings showed that TRAM1 could promote microglia M1 polarization.
authors.affiliation: Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Medical College of Nantong University, Nantong, Jiangsu Province, 226001, China.
authors.forename: Hanxiang
authors.initials: H
authors.lastname: Wang
authors.affiliation: Jiangsu Province Laboratory Animal Center, Medical College of Nantong University, Nantong, Jiangsu Province, 226001, China.
authors.forename: Chun
authors.initials: C
authors.lastname: Liu
authors.affiliation: Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Medical College of Nantong University, Nantong, Jiangsu Province, 226001, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Han
authors.affiliation: Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Medical College of Nantong University, Nantong, Jiangsu Province, 226001, China. 1402339591@qq.com.
authors.forename: Chun
authors.initials: C
authors.lastname: Cheng
authors.affiliation: Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Medical College of Nantong University, Nantong, Jiangsu Province, 226001, China. zdm@ntu.edu.cn.
authors.forename: Dongmei
authors.initials: D
authors.lastname: Zhang
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D002478:Cells, Cultured; D007371:Interferon-gamma / Q000378:metabolism; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics / Q000378:metabolism; D007378:Interleukins / Q000235:genetics / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000166:cytology / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism
chemical_list: D007378:Interleukins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D016328:NF-kappa B; C000611997:TRAM1 protein, mouse; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II; D053592:Interleukin-1 Receptor-Associated Kinases; C507769:Irak1 protein, mouse
keywords: INOS; LPS/IFN-γ; Microglia M1 polarization; TBK; TRAM1