TY - JOUR
T1 - Myeloid-Derived tissue-type plasminogen activator promotes macrophage motility through FAK, Rac1, and NF-κB pathways
AU - Lin, Ling
AU - Jin, Yang
AU - Mars, Wendy M.
AU - Reeves, W. Brian
AU - Hu, Kebin
N1 - Publisher Copyright:
©2014 American Society for Investigative Pathology.
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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.
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U2 - 10.1016/j.ajpath.2014.06.013
DO - 10.1016/j.ajpath.2014.06.013
M3 - Article
C2 - 25131752
AN - SCOPUS:84908644399
SN - 0002-9440
VL - 184
SP - 2757
EP - 2767
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 10
ER -