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American Journal of Respiratory Cell and Molecular Biology. Vol. 34, pp. 645-646, 2006
© 2006 American Thoracic Society
DOI: 10.1165/rcmb.F316

Editorial

Neutrophil-Mediated Eosinophil Transmigration

Parting the Red Sea or Leaving Bread Crumbs

Jeffrey J. Atkinson

Pulmonary and Critical Care Division, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri

Steven D. Shapiro

Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts

Leukocyte migration into tissue has been characterized as a three-step process: (1) rolling, in which weak carbohydrate-mediated adhesions slow the transit of leukocytes on the activated vascular endothelium; (2) arrest, in which stable integrin-mediated adhesions firmly tether the leukocyte to the endothelium; and (3) diapedesis, in which leukocytes pass through the endothelial cells. Leukocyte migration across endothelial barriers may be aided by the endothelial cell, but the basement membrane beneath the endothelial cell is a valid barrier to migration (1). Major determinants of basement membrane migration involve integrin–matrix interactions, chemotactic gradients, and proteolysis.

Chemotactic molecules involved include cytokines, lipid mediators, complement, matrix fragments, and bacterial or viral products. Although some chemotactic molecules trigger nonspecific responses in multiple subsets of leukocytes, a subgroup of cytokines (termed chemokines) are involved in more selective leukocyte accumulation. Chemokines are small negatively charged molecules and many generate a gradient by binding to heparan sulfate proteoglycans (HSPG). This likely allows them to form fixed gradients in tissue by bridging cells–chemokine–HSPGs–extracellular matrix (2). As a result, some stimuli will generate an eosinophil-predominant inflammation, whereas in other instances eosinophils are absent. CXC chemokines with an ELR motif are more specific for neutrophils, while eosinophils respond to chemokine receptor 3 (CCR3) ligating CC chemokines such as eotaxin (CCL11).

In this issue of the Journal, Kikuchi and coworkers (pp. 760–765) describe a scenario in which eosinophil chemotaxis occurs toward the ELR+ CXC chemokine IL-8 (CXCL8) (3). This process was dependent on lipid mediators, TNF-{alpha}, and MMP-9. The use of Matrigel as a barrier representing the basement membrane is a standard technique. The migration of eosinophils across Matrigel (with or without the IL-5) has been studied previously, and MMP-9 was shown to be required for eosinophil migration to the lipid mediator PAF (4). In the present study, neither neutrophil chemotaxis to CXCL8 or eosinophil chemotaxis to CCL11 were dependent on MMP-9 activity. However, following neutrophil migration, the subsequent migration of eosinophils was dependent upon MMP-9 production by the eosinophil (and possibly neutrophils). If neutrophils had already cleared a path, why would the eosinophils need MMP-9? Or perhaps a better question is whether the function of MMP-9 is path clearing at all, as opposed to having an alternative function? (Figure 1)


Figure 1
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  		Figure 1. MMP-9 in eosinophil migration. (A) In the absence of MMP-9 and neutrophils, eosinophils can cross basement membranes in response to CCL11, but are unable to cross or degrade basement membranes in response to CXCL8 or PAF. (B) Co-incubation of eosinophils with neutrophils induces eosinophil chemotaxis in the presence of CXCL8 across basement membranes. Neutrophil migration may modify the basement membrane, release matrix fragments or cytokines, and/or modify cytokine activity. (C) In the absence of MMP-9, neutrophils cross basement membranes in response to CXCL8, but eosinophils do not cross basement membranes. There is a loss of an MMP-9–dependent modification or factor liberation.

 
Matrigel is not simply a wall that needs to be breached, but rather a conglomerate of proteins that have integrin ligands, HSPGs, chemotactic substances, and growth factors (and a little bit of MMP-9). Matrigel is not actually a true basement membrane, but rather a disorganized accumulation of proteins rich in laminin-1, collagen IV, fibronectin, entactin, and perlecan. Cleavage products of laminin, collagen, and entactin have all been shown to be chemotactic for neutrophils and all contain integrin-binding sites (5–7). In addition, the HSPG may provide attachment sites for chemokines like CXCL8. Proteolytic cleavage events in matrigel could expose adhesive sites, release growth factors or chemotactic fragments, or even disengage leukocytes after adhesion. The effect of neutrophils migration through matrigel likely leaves more than just a hole but also a gradient of integrin-binding sites and chemotactic molecules. In addition, neutrophils themselves may react to protease-altered Matrigel by producing cytokines that are not produced in co-incubation alone.

The requirement of MMPs and in particular MMP-9 for leukocyte migration across basement membranes has been a controversial issue. In most studies, investigators have been unable to inhibit neutrophil migration through basement membranes with serine and/or metalloproteinase inhibitors. However, there are reports in which broad spectrum MMP inhibition in vitro is required for leukocyte migration (10, 11). In addition, MMP-9–deficient mice do not have a defect in neutrophil recruitment to multiple stimuli and may actually have an excess recruitment in some models (7–9). Hence, not surprisingly, Kikuchi and coworkers show that both CCL11-induced eosinophil chemotaxis and CXCL8-induced neutrophil chemotaxis through Matrigel are MMP-9 independent. However, in this study, after neutrophil invasion MMP-9 inhibition did decrease subsequent eosinophil migration, to lipid mediators, despite the fact that neutrophils should have cleared paths. This interesting result may in part explain and bridge divergent findings regarding the requirement of MMP-9 in leukocyte recruitment.

MMPs have many important roles in chemotaxis in addition to path clearing degradation of matrix barriers. MMP substrates include a variety of nonmatrix substrates that lead to both activation and degradation of cytokines/chemokines (12–14). MMPs can release cytokines and/or growth factors that are matrix or HSPG bound (15). MMPs can cleave parts of basement membrane molecules, enhancing cellular migration (16), and MMPs can alter the survival of leukocytes once they reach the end organ (possibly by alterations to matrix proteins or cytokines) (17).

With respect to eosinophil chemotaxis, MMP-9 inhibition was more effective than blockade of either LTB4 or PAF receptors and equal to TNF-{alpha} inhibition. In fact, MMP-9 may be part of the TNF pathway by shedding cell surface–bound TNF-{alpha} on neutrophils (18). Conversely, MMP-9 production may also be TNF-{alpha}–mediated. A recent study, using a mouse model in which the ELR+ CXC chemokine Gro{alpha} (CXCL1) was transgenically expressed in Clara cells, was unable to demonstrate a difference in eosinophil migration to Aspergillus conidia despite enhanced neutrophil accumulation (19). In this system, saturation with eosinophil chemokines and the absence of additional disease-specific pathways abrogated neutrophil and MMP-9 contribution to eosinophil migration. Time will tell whether the findings in this study are operative in vivo, and in humans.

MMPs are clearly important in inflammatory cell/eosinophil migration (20), although their "path-clearing" function is not always the primary function. MMPs cleave more than matrix, and matrix molecules are more than structural support. Moreover, our understanding of protein function continues to evolve, and we will continue to rename proteinases and cytokines as long as we insist that their names reflect their "known" function.

Footnotes

Conflict of Interest Statement: Neither author has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

References

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