title: TLR2 Plays a Critical Role in HMGB1-Induced Glomeruli Cell Proliferation Through the FoxO1 Signaling Pathway in Lupus Nephritis.
abstract: The objective of this study was to examine the role and possible mechanisms of toll-like receptor 2 (TLR2) in high-mobility group box chromosomal protein 1 (HMGB1)-induced mouse mesangial cell (MMC) proliferation and glomeruli proliferation of MRL/Fas(lpr) mice. First, the expression of proliferating cell nuclear antigen (PCNA), TLR2 and Forkhead box protein O1 (FoxO1) messenger RNA (mRNA) and protein in the glomeruli of MRL/Fas(lpr) mice was quantified, and the correlation with cell proliferation of glomeruli was analyzed. Then, lipopolysaccharide (LPS), TLR2 neutralization antibody, and small hairpin TLR2 (shTLR2) were used to confirm the role of TLR2 in HMGB1-induced MMC proliferation. Furthermore, wild-type FoxO1 (WT-FoxO1) vector was used to investigate the effect of FoxO1 pathway on HMGB1-induced MMC proliferation. Finally, electroporation was used to knockdown TLR2 in the glomeruli of MRL/Fas(lpr) mice, and renal function, FoxO1, and PCNA expression were detected. The results showed that the TLR2 expression was upregulated and FoxO1 expression was decreased in the glomeruli of MRL/Fas(lpr) mice, and these effects were significantly correlated with cell proliferation of the glomeruli. In vitro, the TLR2 neutralization antibody and the WT-FoxO1 vector, both reduced the MMC proliferation levels induced by HMGB1. The TLR2 neutralization antibody also blocked the HMGB1-dependent activation of the FoxO1 pathway and cell proliferation. In addition, transfection with shTLR2 decreased the proliferation levels and PCNA expression induced by HMGB1. In vivo, treatment with shTLR2 significantly reduced the PCNA expression in the glomeruli of MRL/Fas(lpr) mice and improved renal function. In addition, treatment with shTLR2 or blocking of TLR2 also reduced the translocation of FoxO1. Thus, TLR2 plays a critical role in HMGB1-induced glomeruli cell proliferation through the FoxO1 signaling pathway in lupus nephritis.
authors.affiliation: 1 Department of Pathology, Hebei Key Laboratory of Nephrology, Hebei Medical University , Shijiazhuang, China .
authors.forename: Xiao-juan
authors.initials: XJ
authors.lastname: Feng
authors.affiliation: 1 Department of Pathology, Hebei Key Laboratory of Nephrology, Hebei Medical University , Shijiazhuang, China .
authors.forename: Chao
authors.initials: C
authors.lastname: Wu
authors.affiliation: 2 Department of Rehabilitation, Hebei General Hospital , Shijiazhuang, China .
authors.forename: Gui-fang
authors.initials: GF
authors.lastname: Yan
authors.affiliation: 1 Department of Pathology, Hebei Key Laboratory of Nephrology, Hebei Medical University , Shijiazhuang, China .
authors.forename: Qing-juan
authors.initials: QJ
authors.lastname: Liu
authors.affiliation: 1 Department of Pathology, Hebei Key Laboratory of Nephrology, Hebei Medical University , Shijiazhuang, China .
authors.forename: Jin-xi
authors.initials: JX
authors.lastname: Liu
authors.affiliation: 1 Department of Pathology, Hebei Key Laboratory of Nephrology, Hebei Medical University , Shijiazhuang, China .
authors.forename: Jun
authors.initials: J
authors.lastname: Hao
authors.affiliation: 3 Department of Nephrology, the 2nd Hospital of Hebei Medical University , Shijiazhuang, China .
authors.forename: Ling-ling
authors.initials: LL
authors.lastname: Xing
authors.affiliation: 4 Department of Pathology, Shijiazhuang People's Medical College , Shijiazhuang, China .
authors.forename: Min
authors.initials: M
authors.lastname: Yang
authors.affiliation: 1 Department of Pathology, Hebei Key Laboratory of Nephrology, Hebei Medical University , Shijiazhuang, China .
authors.forename: Shu-xia
authors.initials: SX
authors.lastname: Liu
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D000071161:Forkhead Box Protein O1 / Q000235:genetics / Q000378:metabolism*; D024243:HMGB1 Protein / Q000502:physiology; D006801:Humans; D008181:Lupus Nephritis / Q000276:immunology*; D051379:Mice; D008817:Mice, Mutant Strains; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D019014:fas Receptor / Q000235:genetics
chemical_list: D019138:Antibodies, Blocking; C491899:Fas protein, mouse; D000071161:Forkhead Box Protein O1; D024243:HMGB1 Protein; D018809:Proliferating Cell Nuclear Antigen; D034741:RNA, Small Interfering; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D019014:fas Receptor