Neutrophil slow rolling and intravascular crawling is dependent on the guanine‐exchange factor P‐Rex1

Abstract

Integrin activation is a hallmark for the function of leukocytes and concise trafficking. Here, we investigated the role of P‐Rex1, a Rac‐specific guanine nucleotide exchanging factor, in integrin activation and leukocyte recruitment. We used intravital microscopy of the M. cremaster and the kidney cortex supplemented by in vitro assays of P‐Rex1 knock‐out mice to determine the role of P‐Rex1 in the different steps of leukocyte recruitment and assessed Rac1 activation in a GTP pulldown approach. Finally we subjected P‐Rex1−/− mice to a model of ischemia‐reperfusion induced acute kidney failure to assess physiological consequences of our findings. We report that P‐Rex1 is required for inducing selectin‐mediated LFA‐1 extension, which corresponds to the intermediate affinity conformation and induces slow leukocyte rolling, whereas P‐Rex1 is not involved in the induction of the high‐affinity conformation of LFA‐1 obligatory for leukocyte arrest. Furthermore, we demonstrate that P‐Rex1 is involved in Mac‐1‐dependent intravascular crawling. Mice deficient in P‐Rex1 are protected from ischemia‐reperfusion induced kidney failure.This study was supported by grants from the German Research Foundation (AZ 428/3–1, AZ 428/6–1, SFB 1009/A5 to A.Z and HE‐6810/1–1 to J.H.).