Leukocyte recruitment to the inflamed glomerulus: a critical role for platelet-derived P-selectin in the absence of rolling.
The renal glomerulus is one of the few sites within the microvasculature in which leukocyte recruitment occurs in capillaries. However, due to the difficulty of directly visualizing the glomerulus, the mechanisms of leukocyte recruitment to glomerular capillaries are poorly understood. To overcome this, we rendered murine kidneys hydronephrotic to allow the visualization of the functional glomerular microvasculature during an inflammatory response. These experiments demonstrated that following infusion of anti-glomerular basement membrane (GBM) Ab, leukocytes became adherent in glomerular capillaries via a process of immediate arrest, without undergoing prior detectable rolling. However, despite the absence of rolling, this recruitment involved nonredundant roles for the P-selectin/P-selectin glycoprotein ligand-1 and beta2 integrin/ICAM-1 pathways, suggesting that a novel form of the multistep leukocyte adhesion cascade occurs in these vessels. Anti-GBM Ab also increased glomerular P-selectin expression and induced a P-selectin-independent increase in platelet accumulation. Moreover, platelet depletion prevented both the increase in glomerular P-selectin, and the leukocyte recruitment induced by anti-GBM Ab. Furthermore, depletion of neutrophils and platelets also prevented the increase in urinary protein excretion induced by anti-GBM Ab, indicating that their accumulation in glomeruli contributed to the development of renal injury. Finally, infusion of wild-type platelets into P-selectin-deficient mice restored the ability of glomeruli in these mice to support leukocyte adhesion. Together, these data indicate that anti-GBM Ab-induced leukocyte adhesion in glomeruli occurs via a novel pathway involving a nonrolling interaction mediated by platelet-derived P-selectin.
Kuligowski
Michael P
MP
Centre for Inflammatory Diseases, Department of Medicine, Monash Institute of Medical Research, Monash University, Clayton, Victoria, Australia.
Kitching
A Richard
AR
Hickey
Michael J
MJ
D000818:Animals; D000906:Antibodies / Q000008:administration & dosage; D001323:Autoantibodies; D001485:Basement Membrane / Q000276:immunology / Q000473:pathology; D001792:Blood Platelets / Q000276:immunology / Q000378:metabolism*; D018821:CD18 Antigens / Q000502:physiology; D002448:Cell Adhesion / Q000235:genetics / Q000276:immunology; D002634:Chemotaxis, Leukocyte / Q000235:genetics; D006869:Hydronephrosis / Q000276:immunology / Q000473:pathology*; D007274:Injections, Intraperitoneal; D018799:Intercellular Adhesion Molecule-1 / Q000502:physiology; D007678:Kidney Glomerulus / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D008024:Ligands; D008297:Male; D008562:Membrane Glycoproteins / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019007:P-Selectin / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*
D000906:Antibodies; D001323:Autoantibodies; D018821:CD18 Antigens; D008024:Ligands; D008562:Membrane Glycoproteins; D019007:P-Selectin; C084882:P-selectin ligand protein; C051951:antiglomerular basement membrane antibody; D018799:Intercellular Adhesion Molecule-1