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Originally published online as doi:10.1189/jlb.1007666 on January 3, 2008

Published online before print January 3, 2008
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(Journal of Leukocyte Biology. 2008;83:864-874.)
© 2008 by Society for Leukocyte Biology

Gelatinases mediate neutrophil recruitment in vivo: evidence for stimulus specificity and a critical role in collagen IV remodeling

Christoph A. Reichel*,1, Markus Rehberg*, Peter Bihari*, Christian M. Moser*, Stefan Linder{dagger}, Andrej Khandoga* and Fritz Krombach*

* Institutes for Surgical Research and
{dagger} Cardiovascular Diseases, University of Munich, Munich, Germany

1 Correspondence: Institute for Surgical Research, University of Munich, Marchioninistr. 27, D-81377 Munich, Germany. E-mail: christoph.reichel{at}med.uni-muenchen.de

In the present study, the role of gelatinases [matrix metalloproteinase-2 and -9 (MMP-2 and -9)] for leukocyte rolling, adherence, and transmigration was analyzed in the mouse cremaster muscle under different inflammatory conditions including ischemia-reperfusion (I/R) and stimulation with MIP-1{alpha} or platelet-activating factor (PAF). Using zymography, we detected a significant elevation of MMP-9 activity in response to the stimuli applied, and MMP-2 expression was not altered. However, treatment with a specific MMP-2/-9 inhibitor significantly abrogated elevated MMP-9 activity. As observed by intravital microscopy, all inflammatory conditions induced a significant increase in numbers of adherent and transmigrated leukocytes (>80% Ly-6G+ neutrophils). Blockade of gelatinases significantly diminished I/R- and MIP-1{alpha}-induced leukocyte adherence and subsequent transmigration, and upon stimulation with PAF, gelatinase inhibition had no effect on leukocyte adherence but selectively reduced leukocyte transmigration. Concomitantly, we observed an increase in microvascular permeability after I/R and upon stimulation with MIP-1{alpha} or PAF, which was almost completely abolished in the inhibitor-treated groups. Using immunofluorescence staining and confocal microscopy, discontinuous expression of collagen IV, a major substrate of gelatinases within the perivascular basement membrane (BM), was detected in postcapillary venules. Analysis of intensity profiles demonstrated regions of low fluorescence intensity, whose size was enlarged significantly after I/R and upon stimulation with MIP-1{alpha} or PAF as compared with unstimulated controls. However, this enlargement was abolished significantly after inhibition of gelatinases, respectively. In conclusion, these data demonstrate that gelatinases strictly regulate microvascular permeability and BM remodeling during the early inflammatory response, whereas concomitant leukocyte recruitment is mediated by these proteases in a stimulus-specific manner.

Key Words: leukocyte • transmigration • permeability • basement membrane • gelatinases






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