Blocking of monocyte chemoattractant protein-1 during tubulointerstitial nephritis resulted in delayed neutrophil clearance.
The chemokine monocyte chemoattractant protein (MCP)-1 has been implicated in the monocyte/macrophage infiltration that occurs during tubulointerstitial nephritis (TIN). We investigated the role of MCP-1 in rats with TIN by administering a neutralizing anti-MCP-1 antibody (Ab). We observed significantly reduced macrophage infiltration and delayed neutrophil clearance in the kidneys of TIN model rats treated with the anti-MCP-1 Ab. To exclude the possibility that an observed immune complex could affect the resolution of apoptotic neutrophils via the Fc receptor, TIN model rats were treated with a peptide-based MCP-1 receptor antagonist (RA). The MCP-1 RA had effects similar to those of the anti-MCP-1 Ab. In addition, MCP-1 did not affect macrophage-mediated phagocytosis of neutrophils in vitro. Deposition of the anti-MCP-1 Ab in rat kidneys resulted from its binding to heparan sulfate-immobilized MCP-1, as demonstrated by the detection of MCP-1 in both pull-down and immunoprecipitation assays. We conclude that induction of chemokines, specifically MCP-1, in TIN corresponds with leukocyte infiltration and that the anti-MCP-1 Ab formed an immune complex with heparan sulfate-immobilized MCP-1 in the kidney. Antagonism of MCP-1 in TIN by Ab or RA may alter the pathological process, most likely through delayed removal of apoptotic neutrophils in the inflammatory loci.
Li
Ping
P
Department of Medicine, Renal and Infectious Disease Sections, Baylor College of Medicine, Houston, TX 77030. lfeng@bcm.tmc.edu
Garcia
Gabriela E
GE
Xia
Yiyang
Y
Wu
Wei
W
Gersch
Christine
C
Park
Pyong Woo
PW
Truong
Luan
L
Wilson
Curtis B
CB
Johnson
Richard
R
Feng
Lili
L
D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D000936:Antigen-Antibody Complex; D017209:Apoptosis; D018932:Chemokine CCL2 / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000276:immunology; D018925:Chemokines; D019743:Chemokines, CXC / Q000378:metabolism; D002633:Chemotaxis / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004926:Escherichia coli / Q000378:metabolism; D005355:Fibrosis; D006497:Heparan Sulfate / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D007668:Kidney / Q000276:immunology / Q000378:metabolism; D017737:Macrophages, Peritoneal; D009395:Nephritis, Interstitial / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000187:drug effects / Q000473:pathology*; D010446:Peptide Fragments / Q000276:immunology / Q000494:pharmacology; D010587:Phagocytosis; D051381:Rats; D011914:Rats, Inbred BN; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors; D013997:Time Factors
D000906:Antibodies; D000936:Antigen-Antibody Complex; D018932:Chemokine CCL2; D018925:Chemokines; D019743:Chemokines, CXC; D016207:Cytokines; D006497:Heparan Sulfate; D036341:Intercellular Signaling Peptides and Proteins; D010446:Peptide Fragments; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; C515336:Ccr2 protein, rat; C074302:keratinocyte-derived chemokines