title: CXCR4/CXCL12 hyperexpression plays a pivotal role in the pathogenesis of lupus.
abstract: Among various surface molecules screened, CXCR4 was significantly up-regulated on monocytes, neutrophils, B cell subsets, and plasma cells in multiple murine models of lupus with active nephritis, including B6.Sle1Yaa, BXSB, and MRL.lpr. TLR-mediated signaling and inflammatory cytokines accounted in part for this increase. Increased CXCR4 expression was associated with functional consequences, including increased migration and enhanced B cell survival. Simultaneously, the ligand for CXCR4, CXCL12, was significantly up-regulated in the nephritic kidneys. Treatment with a peptide antagonist of CXCR4 prolonged survival and reduced serum autoantibodies, splenomegaly, intrarenal leukocyte trafficking, and end organ disease in a murine model of lupus. These findings underscore the pathogenic role of CXCR4/CXCL12 in lymphoproliferative lupus and lupus nephritis and highlight this axis as a promising therapeutic target in this disease.
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, 75390, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Wang
authors.forename: Anna-Marie
authors.initials: AM
authors.lastname: Fairhurst
authors.forename: Katalin
authors.initials: K
authors.lastname: Tus
authors.forename: Srividya
authors.initials: S
authors.lastname: Subramanian
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.forename: Fangming
authors.initials: F
authors.lastname: Lin
authors.forename: Peter
authors.initials: P
authors.lastname: Igarashi
authors.forename: Xin J
authors.initials: XJ
authors.lastname: Zhou
authors.forename: Frederic
authors.initials: F
authors.lastname: Batteux
authors.forename: Donald
authors.initials: D
authors.lastname: Wong
authors.forename: Edward K
authors.initials: EK
authors.lastname: Wakeland
authors.forename: Chandra
authors.initials: C
authors.lastname: Mohan
mesh_terms: D000818:Animals; D054377:Chemokine CXCL12 / Q000096:biosynthesis* / Q000276:immunology; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D007150:Immunohistochemistry; D007249:Inflammation / Q000209:etiology / Q000276:immunology / Q000378:metabolism; D007962:Leukocytes / Q000276:immunology* / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000150:complications / Q000276:immunology*; D008181:Lupus Nephritis / Q000209:etiology / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D019718:Receptors, CXCR4 / Q000096:biosynthesis* / Q000276:immunology; D051193:Toll-Like Receptors / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D016207:Cytokines; D019718:Receptors, CXCR4; D051193:Toll-Like Receptors