Gelatinases mediate neutrophil recruitment in vivo: evidence for stimulus specificity and a critical role in collagen IV remodeling.
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Gelatinases mediate neutrophil recruitment in vivo: evidence for stimulus specificity and a critical role in collagen IV remodeling. / Reichel, Christoph A; Rehberg, Markus; Bihari, Peter; Moser, Christian M; Linder, Stefan; Khandoga, Andrej; Krombach, Fritz.
In: J LEUKOCYTE BIOL, Vol. 83, No. 4, 4, 01.04.2008, p. 864-874.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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T1 - Gelatinases mediate neutrophil recruitment in vivo: evidence for stimulus specificity and a critical role in collagen IV remodeling.
AU - Reichel, Christoph A
AU - Rehberg, Markus
AU - Bihari, Peter
AU - Moser, Christian M
AU - Linder, Stefan
AU - Khandoga, Andrej
AU - Krombach, Fritz
PY - 2008/4/1
Y1 - 2008/4/1
N2 - 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-1alpha 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-1alpha-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-1alpha 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-1alpha 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.
AB - 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-1alpha 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-1alpha-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-1alpha 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-1alpha 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.
KW - Animals
KW - Cell Membrane Permeability
KW - Collagen Type IV
KW - Gelatinases
KW - Hemodynamics
KW - Leukocyte Count
KW - Male
KW - Matrix Metalloproteinase 2
KW - Matrix Metalloproteinase 9
KW - Mice
KW - Mice, Inbred C57BL
KW - Neutrophils
KW - Tissue Inhibitor of Metalloproteinase-2
KW - Tissue Inhibitor of Metalloproteinases
U2 - 10.1189/jlb.1007666
DO - 10.1189/jlb.1007666
M3 - SCORING: Journal article
C2 - 18174361
VL - 83
SP - 864
EP - 874
JO - J LEUKOCYTE BIOL
JF - J LEUKOCYTE BIOL
SN - 0741-5400
IS - 4
M1 - 4
ER -