The Journal of Experimental Medicine
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Published online 20 November 2006 doi:10.1084/jem.20060925
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 12, 2569-2575
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BRIEF DEFINITIVE REPORT

 Intraluminal crawling of neutrophils to emigration sites: a molecularly distinct process from adhesion in the recruitment cascade

Mia Phillipson1, Bryan Heit1, Pina Colarusso1, Lixin Liu1, Christie M. Ballantyne2, and Paul Kubes1

1 Immunology Research Group, Department of Physiology and Biophysics, University of Calgary, Calgary T2N 4N1, Alberta, Canada
2 Center for Cardiovascular Disease Prevention, Methodist DeBakey Heart Center and Baylor College of Medicine, Houston, TX 77030

CORRESPONDENCE Paul Kubes: pkubes{at}ucalgary.ca

The prevailing view is that the ß2-integrins Mac-1 ({alpha}Mß2, CD11b/CD18) and LFA-1 ({alpha}Lß2, CD11a/CD18) serve similar biological functions, namely adhesion, in the leukocyte recruitment cascade. Using real-time and time-lapse intravital video-microscopy and confocal microscopy within inflamed microvessels, we systematically evaluated the function of Mac-1 and LFA-1 in the recruitment paradigm. The chemokine macrophage inflammatory protein-2 induced equivalent amounts of adhesion in wild-type and Mac-1–/– mice but very little adhesion in LFA-1–/– mice. Time-lapse video-microscopy within the postcapillary venules revealed that immediately upon adhesion, there is significant intraluminal crawling of all neutrophils to distant emigration sites in wild-type mice. In dramatic contrast, very few Mac-1–/– neutrophils crawled with a 10-fold decrease in displacement and a 95% reduction in velocity. Therefore, Mac-1–/– neutrophils initiated transmigration closer to the initial site of adhesion, which in turn led to delayed transmigration due to movement through nonoptimal emigration sites. Interestingly, the few LFA-1–/– cells that did adhere crawled similarly to wild-type neutrophils. Intercellular adhesion molecule-1 but not intercellular adhesion molecule-2 mediated the Mac-1–dependent crawling. These in vivo results clearly delineate two fundamentally different molecular mechanisms for LFA-1 and Mac-1 in vivo, i.e., LFA-1–dependent adhesion followed by Mac-1–dependent crawling, and both steps ultimately contribute to efficient emigration out of the vasculature.


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