Myeloid-Derived tissue-type plasminogen activator promotes macrophage motility through FAK, Rac1, and NF-κB pathways

Ling Lin, Yang Jin, Wendy M. Mars, W. Brian Reeves, Kebin Hu

Research output: Contribution to journalArticle

14 Scopus citations

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 marrowederived 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-1especific 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-FAKepositive 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.

Original languageEnglish (US)
Pages (from-to)2757-2767
Number of pages11
JournalAmerican Journal of Pathology
Volume184
Issue number10
DOIs
StatePublished - 2014
Externally publishedYes

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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