Myeloid-derived tissue-type plasminogen activator promotes macrophage motility through FAK, Rac1, and NF-κB pathways
Ling Lin1, Yang Jin2, Wendy M Mars3
1Division of Nephrology, Department of Medicine, Penn State University College of Medicine, Hershey, Pennsylvania.
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.
Insights
Tissue-type plasminogen activator (tPA) drives kidney disease by promoting macrophage migration. Myeloid-derived tPA utilizes a novel FAK, Rac-1, and NF-κB pathway to enhance macrophage motility and infiltration in the kidneys.
Area of Science:
- Nephrology
- Immunology
- Cell Biology
Background:
- Macrophage accumulation is a key feature of progressive kidney disease.
- Tissue-type plasminogen activator (tPA) is implicated in macrophage infiltration and renal inflammation in chronic kidney injury, but the mechanism is unclear.
Purpose of the Study:
- To investigate the role of tPA in macrophage motility and infiltration in kidney injury.
- To elucidate the molecular mechanisms by which tPA influences macrophage migration.
Main Methods:
- Tracking fluorescence-labeled bone marrow-derived macrophages in tPA-deficient and wild-type mice.
- Bone marrow chimeric mouse experiments to identify the source of endogenous tPA.
- In vitro studies assessing macrophage motility with tPA, CD11b, focal adhesion kinase (FAK), Rac-1, and NF-κB inhibitors.
- In vivo analysis of phospho-FAK and Rac-1 activity in kidney tissues.
Main Results:
- tPA-deficient mice showed significantly reduced macrophage infiltration compared to wild-type mice.
- Myeloid cells were identified as the primary source of endogenous tPA promoting macrophage migration.
- tPA enhanced macrophage motility in a protease-independent, CD11b-mediated manner.
- FAK, Rac-1, and NF-κB signaling pathways were essential for tPA-induced macrophage migration, with ectopic FAK mimicking tPA's effect.
- tPA activated FAK and Rac-1 signaling in vivo, with reduced phospho-FAK and Rac-1 activity observed in tPA knockout mice.
Conclusions:
- Myeloid-derived tPA promotes macrophage migration through a novel signaling cascade involving FAK, Rac-1, and NF-κB.
- Targeting this tPA-mediated pathway could offer therapeutic strategies for kidney diseases characterized by macrophage infiltration.
More Related Videos
07:55A Macrophage Reporter Cell Assay to Examine Toll-Like Receptor-Mediated NF-kB/AP-1 Signaling on Adsorbed Protein Layers on Polymeric Surfaces
Published on: January 7, 2020
10:43Methods to Study Mrp4-containing Macromolecular Complexes in the Regulation of Fibroblast Migration
Published on: May 19, 2016
Related Concept Videos
01:17Intracellular Signaling Affects Focal Adhesions
Some...
01:39Mechanism of Filopodia Formation
Their main function is to guide migrating cells during normal tissue morphogenesis or cancer metastasis by recognizing and making initial contacts with the extracellular matrix. However, they can also act as stationary cell anchors or help to establish communication...
01:31Mechanism of Lamellipodia Formation
01:07MAPK Signaling Cascades