title: Deposition of microparticles by neutrophils onto inflamed epithelium: a new mechanism to disrupt epithelial intercellular adhesions and promote transepithelial migration.
abstract: Neutrophil [polymorphonuclear leukocyte (PMN)] transepithelial migration (TEM) is a hallmark of inflammatory mucosal disorders. PMN TEM is associated with epithelial injury; however, mechanisms involved in this process are not well defined. The current work describes a new mechanism whereby deposition of PMN membrane-derived microparticles (PMN-MPs) onto intestinal epithelial cells (IECs) during TEM leads to loss of epithelial cadherins, thus promoting epithelial injury and increased PMN recruitment. PMN-MPs secreted by activated PMNs during TEM displayed a high level of enzymatically active matrix metalloproteinase 9 (MMP-9), and were capable of mediating potent effects on IEC integrity. Isolated PMN-MPs efficiently bound to IEC monolayers and induced cleavage of desmoglein-2 (DSG-2) but not E-cadherin, leading to disruption of IEC intercellular adhesions. Furthermore, PMN-MP binding to intestinal epithelium in vitro in transwell assays and in vivo in ligated intestinal loop preparations facilitated increases in PMN TEM. These effects were MMP-9 dependent and were reversed in the presence of specific pharmacological inhibitors. Finally, we demonstrated that IEC Dsg-2 serves as a barrier for migrating PMNs, and its removal by PMN-MP-associated MMP-9 facilitates PMN trafficking across epithelial layers. Our findings thus implicate PMN-MPs in PMN-mediated inflammation and epithelial damage, as observed in inflammatory disorders of mucosal surfaces.-Butin-Israeli, V., Houser, M. C., Feng, M., Thorp, E. B., Nusrat, A., Parkos, C. A, Sumagin, R. Deposition of microparticles by neutrophils onto inflamed epithelium: a new mechanism to disrupt epithelial intercellular adhesions and promote transepithelial migration.
authors.affiliation: Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
authors.forename: Veronika
authors.initials: V
authors.lastname: Butin-Israeli
authors.affiliation: Department of Physiology, Emory University School of Medicine, Atlanta, Georgia, USA; and.
authors.forename: Madelyn C
authors.initials: MC
authors.lastname: Houser
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: Mingli
authors.initials: M
authors.lastname: Feng
authors.affiliation: Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
authors.forename: Edward B
authors.initials: EB
authors.lastname: Thorp
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: Asma
authors.initials: A
authors.lastname: Nusrat
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Parkos
authors.affiliation: Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA; ronen.sumagin@northwestern.edu.
authors.forename: Ronen
authors.initials: R
authors.lastname: Sumagin
mesh_terms: D000818:Animals; D015820:Cadherins / Q000378:metabolism; D002448:Cell Adhesion; D055252:Cell-Derived Microparticles / Q000378:metabolism; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000166:cytology*; D004848:Epithelium / Q000378:metabolism*; D006801:Humans; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000378:metabolism*; D057705:Transendothelial and Transepithelial Migration / Q000502:physiology*
chemical_list: D015820:Cadherins
keywords: barrier; inflammation; injury; intestine; transmigration