title: Myeloid-derived tissue-type plasminogen activator promotes macrophage motility through FAK, Rac1, and NF-κB pathways.
abstract: Macrophage accumulation is one of the hallmarks of progressive kidney disease. Tissue-type plasminogen activator (tPA) is known to promote macrophage infiltration and renal inflammation during chronic kidney injury. However, the underlying mechanism remains largely unknown. We examined the role of tPA in macrophage motility in vivo by tracking fluorescence-labeled bone marrow-derived macrophages, and found that tPA-deficient mice had markedly fewer infiltrating fluorescence-labeled macrophages than the wild-type (WT) mice. Experiments in bone marrow chimeric mice further demonstrated that myeloid cells are the main source of endogenous tPA that promotes macrophage migration. In vitro studies showed that tPA promoted macrophage motility through its CD11b-mediated protease-independent function; and focal adhesion kinase (FAK), Rac-1, and NF-κB were indispensable to tPA-induced macrophage migration as either infection of FAK dominant-negative adenovirus or treatment with a Rac-1-specific inhibitor or NF-κB inhibitor abolished the effect of tPA. Moreover, ectopic FAK mimicked tPA and induced macrophage motility. tPA also activated migratory signaling in vivo. The accumulation of phospho-FAK-positive CD11b macrophages in the obstructed kidneys from WT mice was clearly attenuated in tPA knockout mice, which also displayed lower Rac-1 activity than their WT counterparts. Therefore, our results indicate that myeloid-derived tPA promotes macrophage migration through a novel signaling cascade involving FAK, Rac-1, and NF-κB.
authors.affiliation: Division of Nephrology, Department of Medicine, Penn State University College of Medicine, Hershey, Pennsylvania.
authors.forename: Ling
authors.initials: L
authors.lastname: Lin
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Yang
authors.initials: Y
authors.lastname: Jin
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Wendy M
authors.initials: WM
authors.lastname: Mars
authors.affiliation: Division of Nephrology, Department of Medicine, Penn State University College of Medicine, Hershey, Pennsylvania.
authors.forename: W Brian
authors.initials: WB
authors.lastname: Reeves
authors.affiliation: Division of Nephrology, Department of Medicine, Penn State University College of Medicine, Hershey, Pennsylvania. Electronic address: kebinhu@hmc.psu.edu.
authors.forename: Kebin
authors.initials: K
authors.lastname: Hu
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D002678:Chimera; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D009479:Neuropeptides / Q000378:metabolism*; D015398:Signal Transduction; D010959:Tissue Plasminogen Activator / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; D009479:Neuropeptides; C484602:Rac1 protein, mouse; D051417:Focal Adhesion Kinase 1; C496051:Ptk2 protein, mouse; D010959:Tissue Plasminogen Activator; D020830:rac1 GTP-Binding Protein