Chemokine receptor Ccr2 deficiency reduces renal disease and prolongs survival in MRL/lpr lupus-prone mice.
MRL/MpJ-Fas(lpr)/J (MRL/lpr) mice represent a well-established mouse model of human systemic lupus erythematosus. MRL/lpr mice homozygous for the spontaneous lymphoproliferation mutation (lpr) are characterized by systemic autoimmunity, massive lymphadenopathy associated with proliferation of aberrant T cells, splenomegaly, hypergammaglobulinemia, arthritis, and fatal immune complex-mediated glomerulonephritis. It was reported previously that steady-state mRNA levels for the chemokine (C-C motif) receptor 2 (Ccr2) continuously increase in kidneys of MRL/lpr mice. For examining the role of Ccr2 for development and progression of immune complex-mediated glomerulonephritis, Ccr2-deficient mice were generated and backcrossed onto the MRL/lpr genetic background. Ccr2-deficient MRL/lpr mice developed less lymphadenopathy, had less proteinuria, had reduced lesion scores, and had less infiltration by T cells and macrophages in the glomerular and tubulointerstitial compartment. Ccr2-deficient MRL/lpr mice survived significantly longer than MRL/lpr wild-type mice despite similar levels of circulating immunoglobulins and comparable immune complex depositions in the glomeruli of both groups. Anti-dsDNA antibody levels, however, were reduced in the absence of Ccr2. The frequency of CD8+ T cells in peripheral blood was significantly lower in Ccr2-deficient MRL/lpr mice. Thus Ccr2 deficiency influenced not only monocyte/macrophage and T cell infiltration in the kidney but also the systemic T cell response in MRL/lpr mice. These data suggest an important role for Ccr2 both in the general development of autoimmunity and in the renal involvement of the lupus-like disease. These results identify Ccr2 as an additional possible target for the treatment of lupus nephritis.
Pérez de Lema
Guillermo
G
Klinikum der Universität München, Medizinische Poliklinik - Innenstadt, Munich, Germany.
Maier
Holger
H
Franz
Tobias J
TJ
Escribese
Maríia
M
Chilla
Silvia
S
Segerer
Stephan
S
Camarasa
Natalia
N
Schmid
Holger
H
Banas
Bernhard
B
Kalaydjiev
Svetoslav
S
Busch
Dirk H
DH
Pfeffer
Klaus
K
Mampaso
Francisco
F
Schlöndorff
Detlef
D
Luckow
Bruno
B
D000818:Animals; D001707:Biopsy, Needle; D004195:Disease Models, Animal; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D019085:Fluorescent Antibody Technique, Direct; D007150:Immunohistochemistry; D008180:Lupus Erythematosus, Systemic / Q000276:immunology / Q000473:pathology; D008181:Lupus Nephritis / Q000276:immunology* / Q000401:mortality / Q000473:pathology*; D051379:Mice; D019463:Mice, Inbred MRL lpr; D019707:Receptors, Chemokine / Q000172:deficiency* / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012307:Risk Factors; D012680:Sensitivity and Specificity; D015996:Survival Rate
D019707:Receptors, Chemokine