Anti‐myeloperoxidase antibodies rapidly induce α4 integrin‐dependent glomerular neutrophil adhesion

Abstract

Despite the fact that anti‐myeloperoxidase antibodies (anti‐MPO) have been shown to promote leukocyte adhesion in flow‐based assays in vitro and in postcapillary venules in vivo, their role in promoting adhesion in the glomerular vasculature is less clear. We used renal intravital microscopy to examine glomerular leukocyte adhesion induced by anti‐MPO. In mice pretreated with LPS, 50 μg of anti‐MPO induced LFA‐1‐dependent adhesion in glomeruli. In concert with this finding, in mice pretreated with LPS, ~75% of circulating neutrophils bound anti‐MPO within 5 min of intravenous administration. However, even in the absence of LPS pretreatment, ~50% of circulating neutrophils bound anti‐MPO, a response not seen in MPO−/− mice. In addition, a higher dose of anti‐MPO (200 μg) induced robust glomerular leukocyte adhesion in the absence of LPS pretreatment. The latter response was β2‐integrin‐independent, instead requiring the α4‐integrin, which was upregulated on neutrophils in response to anti‐MPO. These data indicate that anti‐MPO antibodies are capable of inducing glomerular leukocyte adhesion via multiple pathways, with lower doses only inducing adhesion in mice receiving an infection‐related stimulus, and higher doses being capable of inducing responses in the absence of an additional inflammatory stimulus, via alternative adhesion mechanisms.Supported by the NHMRC (Australia) & Genzyme