CXCR4 regulates migration of lung alveolar epithelial cells through activation of Rac1 and matrix metalloproteinase-2

Ghosh, Manik C.; Makena, Patrudu S.; Gorantla, Vijay K.; Sinclair, Scott E.; Waters, Christopher M.

doi:10.1152/ajplung.00321.2011

Cited by 58 publications

(54 citation statements)

References 60 publications

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“…The significant association between lung CXCL12 concentrations and fibrocyte numbers in our model supports previous studies that demonstrated the importance of CXCL12 in fibrocyte recruitment (12,13). CXCL12 secretion is induced in rat Type II epithelial cells after scratch injury, implicating the epithelium as an important source of CXCL12 (38). In patients with IPF, epithelial cells expressed CXCL12 at higher concentrations than in control samples (14).…”

Section: Discussionsupporting

confidence: 88%

Regulatory T Cells Reduce Acute Lung Injury Fibroproliferation by Decreasing Fibrocyte Recruitment

Garibaldi

D’Alessio

Mock

et al. 2013

Am J Respir Cell Mol Biol

155

135

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Acute lung injury (ALI) causes significant morbidity and mortality. Fibroproliferation in ALI results in worse outcomes, but the mechanisms governing fibroproliferation remain poorly understood. Regulatory T cells (Tregs) are important in lung injury resolution. Their role in fibroproliferation is unknown. We sought to identify the role of Tregs in ALI fibroproliferation, using a murine model of lung injury. Wild-type (WT) and lymphocyte-deficient Rag-1 2/2 mice received intratracheal LPS. Fibroproliferation was characterized by histology and the measurement of lung collagen. Lung fibrocytes were measured by flow cytometry. To dissect the role of Tregs in fibroproliferation, Rag-1 2/2 mice received CD4 1 CD25 1 (Tregs) or CD4 1 CD252 Tcells (non-Tregs) at the time of LPS injury. To define the role of the chemokine (C-X-C motif) ligand 12 (CXCL12)-CXCR4 pathway in ALI fibroproliferation, Rag-1 2/2 mice were treated with the CXCR4 antagonist AMD3100 to block fibrocyte recruitment. WT and Rag-1 2/2 mice demonstrated significant collagen deposition on Day 3 after LPS. WT mice exhibited the clearance of collagen, but Rag-1 2/2 mice developed persistent fibrosis. This fibrosis was mediated by the sustained epithelial expression of CXCL12 (or stromal cell-derived factor 1 [SDF-1]) that led to increased fibrocyte recruitment. The adoptive transfer of Tregs resolved fibroproliferation by decreasing CXCL12 expression and subsequent fibrocyte recruitment. Blockade of the CXCL12-CXCR4 axis with AMD3100 also decreased lung fibrocytes and fibroproliferation. These results indicate a central role for Tregs in the resolution of ALI fibroproliferation by reducing fibrocyte recruitment along the CXCL12-CXCR4 axis. A dissection of the role of Tregs in ALI fibroproliferation may inform the design of new therapeutic tools for patients with ALI.Keywords: acute lung injury; fibroproliferative ARDS; fibrocytes; regulatory T cells; lung injury resolution Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) affect 190,000 individuals in the United States each year, accounting for 75,000 deaths (1). The only treatment that improves outcomes involves a lung-protective strategy in patients on mechanical ventilation (2). Mortality from ALI/ARDS remains as high as 44% (3).ALI/ARDS is divided into an exudative phase marked by edema fluid, hyaline membrane formation, and neutrophilic infiltration, followed in some patients by a fibroproliferative phase (4). Fibroproliferation is part of the normal repair response, and is characterized by the intra-alveolar accumulation of fibroblasts and collagen deposition. If this process is ineffective or continues unabated, patients may develop fibrosis (5). Longer durations of ARDS correspond to increased lung collagen and fibrosis, and portend worse outcomes (6). Fibroproliferative changes on biopsy and computed tomography predict mortality (7,8). The determinants of prolonged fibroproliferation and factors that govern its resolution remain poorly understood.The fibroblast is a key cell ...

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Section: Discussionsupporting

confidence: 88%

Regulatory T Cells Reduce Acute Lung Injury Fibroproliferation by Decreasing Fibrocyte Recruitment

Garibaldi

D’Alessio

Mock

et al. 2013

Am J Respir Cell Mol Biol

155

135

View full text Add to dashboard Cite

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“…The kinetics of the relative wound density (RWD) was analyzed by IncuCyte TM software. Wound Healing Assay-Cell migration was measured according to the previously described method (16). In brief, the confluent monolayers of fibroblast cells were wounded by scraping with a pipette tip across the monolayer.…”

Section: Animals-mrp4mentioning

confidence: 99%

Multi-drug Resistance Protein 4 (MRP4)-mediated Regulation of Fibroblast Cell Migration Reflects a Dichotomous Role of Intracellular Cyclic Nucleotides

Sinha

Ren

Arora

et al. 2013

Journal of Biological Chemistry

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Background: MRP4 is an endogenous transporter of cyclic nucleotides that can regulate cell migration. The role of MRP4 in fibroblast migration is unknown. Results: MRP4-deficient fibroblasts migrate faster and have a moderately higher level of intracellular cyclic nucleotides. Conclusion: Inhibition of MRP4 increases fibroblast migration via alteration of intracellular cyclic nucleotide levels. Significance: Inhibition of MRP4 facilitates wound repair.

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“…Chemokines are also important regulators of Rac1, one of them, CXCL12 (also known as SDF-1a) activates Rac1, decreases cAMP levels, and favors prostate cancer cells migration (21)(22)(23). In addition, CXCR4, the CXCL12 receptor, is frequently overexpressed in malignant epithelial cells, and the CXCL12/CXCR4 axis plays a pivotal role in directing the metastasis of CXCR4-positive tumor cells to organs that express CXCL12, such as lungs, liver, and bones (24,25).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of the GTPase Rac1 Mediates the Antimigratory Effects of Metformin in Prostate Cancer Cells

Dirat

Ader

Golzio

et al. 2015

Molecular Cancer Therapeutics

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Cell migration is a critical step in the progression of prostate cancer to the metastatic state, the lethal form of the disease. The antidiabetic drug metformin has been shown to display antitumoral properties in prostate cancer cell and animal models; however, its role in the formation of metastases remains poorly documented. Here, we show that metformin reduces the formation of metastases to fewer solid organs in an orthotopic metastatic prostate cancer cell model established in nude mice. As predicted, metformin hampers cell motility in PC3 and DU145 prostate cancer cells and triggers a radical reorganization of the cell cytoskeleton. The small GTPase Rac1 is a master regulator of cytoskeleton organization and cell migration. We report that metformin leads to a major inhibition of Rac1 GTPase activity by interfering with some of its multiple upstream signaling pathways, namely P-Rex1 (a Guanine nucleotide exchange factor and activator of Rac1), cAMP, and CXCL12/CXCR4, resulting in decreased migration of prostate cancer cells. Importantly, overexpression of a constitutively active form of Rac1, or P-Rex, as well as the inhibition of the adenylate cyclase, was able to reverse the antimigratory effects of metformin. These results establish a novel mechanism of action for metformin and highlight its potential antimetastatic properties in prostate cancer. Mol Cancer Ther; 14(2); 586-96. Ó2014 AACR.

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CXCR4 regulates migration of lung alveolar epithelial cells through activation of Rac1 and matrix metalloproteinase-2

Cited by 58 publications

References 60 publications

Regulatory T Cells Reduce Acute Lung Injury Fibroproliferation by Decreasing Fibrocyte Recruitment

Regulatory T Cells Reduce Acute Lung Injury Fibroproliferation by Decreasing Fibrocyte Recruitment

Multi-drug Resistance Protein 4 (MRP4)-mediated Regulation of Fibroblast Cell Migration Reflects a Dichotomous Role of Intracellular Cyclic Nucleotides

Inhibition of the GTPase Rac1 Mediates the Antimigratory Effects of Metformin in Prostate Cancer Cells

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