Abstract

The inflammatory response is a double-edged sword. Mobilization of leukocytes to a focus of inflammation is critical for the rapid resolution of infections and restoration of tissue damage resulting from a variety of injuries. On the other hand, most human pathology results from inflammation that is misdirected or prolonged with the result that host tissues are damaged as a result. Therefore, much attention has been directed toward understanding the molecular basis of inflammation in the hope of being better able to regulate it. Previous studies have demonstrated a crucial role for platelet/endothelial cell adhesion molecule-2 (PECAM) in transendothelial migration (TEM), the step in which leukocytes (WBC) enter inflamed tissues by squeezing between the tightly apposed endothelial cells (EC) lining the blood vessels. However, even under the most favorable circumstances, blocking PECAM function only blocks 80-90% of leukocyte influx. The residual 10-20% of WBC that are not blocked may represent a clinically significant population under chronic conditions. Furthermore, there may be inflammatory stimuli, vascular beds, or WBC types for which PECAM does not play a major role in TEM.
The aims of this proposal are to identify molecules responsible for PECAM-independent (PECAM alternative) mechanisms of TEM. We have developed an in vitro assay that can distinguish a block in adhesion of WBC tot he apical surface of EC from a block in TEM. Using this assay, we have identified two candidate molecules.
In aim 1 we will further characterize and clone HEC2, a novel membrane proteins on EBC and EC junctions that are involved in TEM.
In aim 2, we will further characterize a leukocyte beta2 integrin that plays a unique role in TEM that is independent of its role in adhesion and dependent on blockade of PECAM.
In aim 3, we will test predictions made in vitro in two murine models of acute inflammation in which we can distinguish a block in adhesion from a block in transmigration. We have generated mice that are genetically deficient in PECAM and mice in which PECAM does not function. These mice will be critical to evaluate PECAM-independent TEM.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL064774-02
Application #
6390706
Study Section
Pathology A Study Section (PTHA)
Program Officer
Applebaum-Bowden, Deborah
Project Start
2000-04-01
Project End
2004-03-31
Budget Start
2001-04-01
Budget End
2002-03-31
Support Year
2
Fiscal Year
2001
Total Cost
$392,625
Indirect Cost

  Institution

Name
Weill Medical College of Cornell University
Department
Pathology
Type
Schools of Medicine
DUNS #
201373169
City
New York
State
NY
Country
United States
Zip Code
10065

  Publications

Sullivan, David P; Bui, Triet; Muller, William A et al. (2018) In vivo imaging reveals unique neutrophil transendothelial migration patterns in inflamed intestines. Mucosal Immunol 11:1571-1581
Early, Merideth; Schroeder, William G; Unnithan, Ranajana et al. (2017) Differential effect of Platelet Endothelial Cell Adhesion Molecule-1 (PECAM-1) on leukocyte infiltration during contact hypersensitivity responses. PeerJ 5:e3555
Weber, Evan W; Muller, William A (2017) Roles of transient receptor potential channels in regulation of vascular and epithelial barriers. Tissue Barriers 5:e1331722
DeBerge, Matthew; Yeap, Xin Yi; Dehn, Shirley et al. (2017) MerTK Cleavage on Resident Cardiac Macrophages Compromises Repair After Myocardial Ischemia Reperfusion Injury. Circ Res 121:930-940
Winger, Ryan C; Harp, Christopher T; Chiang, Ming-Yi et al. (2016) Cutting Edge: CD99 Is a Novel Therapeutic Target for Control of T Cell-Mediated Central Nervous System Autoimmune Disease. J Immunol 196:1443-8
Muller, William A (2016) Transendothelial migration: unifying principles from the endothelial perspective. Immunol Rev 273:61-75
Muller, William A (2016) How monocytes guard the glomerulus. Proc Natl Acad Sci U S A 113:10453-5
Sullivan, David P; Watson, Richard L; Muller, William A (2016) 4D intravital microscopy uncovers critical strain differences for the roles of PECAM and CD99 in leukocyte diapedesis. Am J Physiol Heart Circ Physiol 311:H621-32
Maisa, Anna; Hearps, Anna C; Angelovich, Thomas A et al. (2015) Monocytes from HIV-infected individuals show impaired cholesterol efflux and increased foam cell formation after transendothelial migration. AIDS 29:1445-57
Rutledge, Nakisha S; Weber, Evan W; Winger, Ryan et al. (2015) CD99-like 2 (CD99L2)-deficient mice are defective in the acute inflammatory response. Exp Mol Pathol 99:455-9

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