CXCR4/CXCL12 hyperexpression plays a pivotal role in the pathogenesis of lupus.
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.
Wang
Andrew
A
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, 75390, USA.
Fairhurst
Anna-Marie
AM
Tus
Katalin
K
Subramanian
Srividya
S
Liu
Yang
Y
Lin
Fangming
F
Igarashi
Peter
P
Zhou
Xin J
XJ
Batteux
Frederic
F
Wong
Donald
D
Wakeland
Edward K
EK
Mohan
Chandra
C
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
C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D016207:Cytokines; D019718:Receptors, CXCR4; D051193:Toll-Like Receptors