title: The pattern recognition receptor, Mincle, is essential for maintaining the M1 macrophage phenotype in acute renal inflammation.
abstract: Mincle (macrophage-inducible C-type lectin, Clec4e) is a transmembrane pattern recognition receptor involving the innate immunity, but its role in kidney disease is still unexplored. In the obstructed kidney of the unilateral ureteral obstruction model of renal injury, Mincle was specifically detected in the infiltrating M1 macrophages (CD68+iNOS+cells) on day one but was rapidly reduced following reduction of M1 macrophages during the progression of kidney injury. Interestingly, Mincle-expressing macrophages were progressively increased in the cisplatin-induced acute kidney injury model, where iNOS expression was detected in the CD68+cells following Mincle induction. Adaptive transfer of Mincle+M1 macrophages largely promoted cisplatin-induced renal inflammation, which was prevented by the knockdown of Mincle in the transferred cells. Mincle was tightly regulated by TLR4/NF-κB signaling as evidenced by the binding of NF-κB/p65 to the promoter region of Mincle in LPS-primed macrophages. Blocking TLR4 or NF-κB suppressed LPS-induced Mincle expression on macrophages. Importantly, Mincle was found to be essential for maintaining the inflammatory phenotypes of M1 macrophages through the Syk signaling pathway since knockdown of Mincle or inhibition of Syk suppressed LPS-induced IL-1β, MCP-1, and iNOS expression. Thus, Mincle is induced specifically on M1 macrophages, where Mincle-Syk signaling promotes and maintains inflammatory phenotypes of M1 macrophages in acute renal inflammation. Hence, targeting Mincle may be a novel therapy for acute kidney injury associated with M1 macrophages.
authors.affiliation: Li Ka Shing Institute of Health Sciences, and Department of Medicine and Therapeutics, and Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China; Institute of Nephrology, School of Medicine, ZhongDa Hospital, Southeast University, Nanjing, China.
authors.forename: Lin L
authors.initials: LL
authors.lastname: Lv
authors.affiliation: Li Ka Shing Institute of Health Sciences, and Department of Medicine and Therapeutics, and Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China; Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China.
authors.forename: Patrick Ming-Kuen
authors.initials: PM
authors.lastname: Tang
authors.affiliation: Li Ka Shing Institute of Health Sciences, and Department of Medicine and Therapeutics, and Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China.
authors.forename: Chun J
authors.initials: CJ
authors.lastname: Li
authors.affiliation: Li Ka Shing Institute of Health Sciences, and Department of Medicine and Therapeutics, and Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China.
authors.forename: Yong K
authors.initials: YK
authors.lastname: You
authors.affiliation: Li Ka Shing Institute of Health Sciences, and Department of Medicine and Therapeutics, and Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China.
authors.forename: Jinhong
authors.initials: J
authors.lastname: Li
authors.affiliation: Li Ka Shing Institute of Health Sciences, and Department of Medicine and Therapeutics, and Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China.
authors.forename: Xiao-Ru
authors.initials: XR
authors.lastname: Huang
authors.affiliation: Li Ka Shing Institute of Health Sciences, and Department of Medicine and Therapeutics, and Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Ni
authors.affiliation: Li Ka Shing Institute of Health Sciences, and Department of Medicine and Therapeutics, and Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China.
authors.forename: Min
authors.initials: M
authors.lastname: Feng
authors.affiliation: Institute of Nephrology, School of Medicine, ZhongDa Hospital, Southeast University, Nanjing, China. Electronic address: liubc64@163.com.
authors.forename: Bi C
authors.initials: BC
authors.lastname: Liu
authors.affiliation: Li Ka Shing Institute of Health Sciences, and Department of Medicine and Therapeutics, and Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China. Electronic address: hylan@cuhk.edu.hk.
authors.forename: Hui-Yao
authors.initials: HY
authors.lastname: Lan
mesh_terms: D058186:Acute Kidney Injury / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D019264:Adoptive Transfer; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D001665:Binding Sites; D002945:Cisplatin; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006801:Humans; D007668:Kidney / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D037181:Lectins, C-Type / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000637:transplantation; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009393:Nephritis / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010641:Phenotype; D011401:Promoter Regions, Genetic; D000067996:RAW 264.7 Cells; D034622:RNA Interference; D051192:Receptors, Pattern Recognition / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction; D000072377:Syk Kinase / Q000378:metabolism; D013997:Time Factors; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism; D014162:Transfection; D014517:Ureteral Obstruction / Q000150:complications; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D002945:Cisplatin; D037181:Lectins, C-Type; D008565:Membrane Proteins; D052247:Nitric Oxide Synthase Type II; D051192:Receptors, Pattern Recognition; D000072377:Syk Kinase; D051197:Toll-Like Receptor 4; D051996:Transcription Factor RelA; C081026:CD68 protein, mouse; D000097382:CD68 Molecule; C113583:Clecsf8 protein, mouse; C498144:Rela protein, mouse; C493487:Tlr4 protein, mouse; C496317:Nos2 protein, mouse; C000606897:Syk protein, mouse
keywords: Clec4e; M1 macrophage; Mincle; TLR4/NF-κB/Syk signaling; acute kidney injury; inflammation; macrophage-inducible C-type lectin