title: Impaired B cell inhibition by lupus bone marrow mesenchymal stem cells is caused by reduced CCL2 expression.
abstract: Mesenchymal stem cells (MSC) from healthy human and normal mice can inhibit normal B cell proliferation, differentiation, and Ab secretion in vitro. However, it remains unknown whether MSC from lupus-like mice and patients with systemic lupus erythematosus (SLE) exhibit the same immunoregulatory activity as normal MSC for B cell inhibition and, if not, what the underlying molecular mechanism would be. In this study, we showed that bone marrow-derived MSCs from lupus-like mice and SLE patients had an impairment in suppressing normal B cell proliferation and differentiation, which was caused by the reduction of CCL2 levels. Knockdown of CCL2 in normal MSC damaged their suppressive capacity for B cells. Conversely, overexpression of CCL2 in lupus MSCs restored their immunoregulatory ability for B cells in vitro and ameliorated the pathology of lupus nephritis and serological changes in MRL/lpr mice in vivo. Mechanistically, MSC-mediated B cell inhibition was dependent on matrix metalloproteinase proteolytic processing of CCL2. These findings reveal a novel function of CCL2 in B cell regulation by MSCs and suggest that CCL2 manipulation on MSCs may serve as a potential pathway for developing the more effective MSC-based therapy in autoimmune diseases associated with B cell activation, such as SLE.
authors.affiliation: Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210008, People's Republic of China;
authors.forename: Nan
authors.initials: N
authors.lastname: Che
authors.affiliation: Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210008, People's Republic of China;
authors.forename: Xia
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210008, People's Republic of China;
authors.forename: Lu
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210008, People's Republic of China;
authors.forename: Rui
authors.initials: R
authors.lastname: Liu
authors.affiliation: Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210008, People's Republic of China;
authors.forename: Haifeng
authors.initials: H
authors.lastname: Chen
authors.affiliation: Model Animal Research Center, Nanjing University, Nanjing, Jiangsu 210093, People's Republic of China;
authors.forename: Xiang
authors.initials: X
authors.lastname: Gao
authors.affiliation: Center for Craniofacial Molecular Biology, Herman Ostrow School of Dentistry of USC, University of Southern California, Los Angeles, CA 90033;
authors.forename: Songtao
authors.initials: S
authors.lastname: Shi
authors.affiliation: Mucosal Immunology Section, Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Wanjun
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210008, People's Republic of China; lingyunsun2012@163.com.
authors.forename: Lingyun
authors.initials: L
authors.lastname: Sun
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology; D001854:Bone Marrow Cells / Q000276:immunology* / Q000473:pathology; D002450:Cell Communication / Q000276:immunology; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000276:immunology; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D059748:Proteolysis; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014184:Transplantation, Homologous
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D034741:RNA, Small Interfering; D020782:Matrix Metalloproteinases