Rho-specific Guanine nucleotide exchange factors (Rho-GEFs) inhibition affects macrophage phenotype and disrupts Golgi complex |
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| Affiliation: | 1. The Houston Methodist Research Institute, Houston, TX, USA;2. Department of Nephrology, Second Xiangya Hospital, Central South University, Changsha 410011, China;3. The Houston Methodist Hospital, Department of Surgery, Houston, TX, USA;4. CNRS UMR 6290, Institute of Genetics and Development of Rennes, Cell Cycle Group, IFR 140 GFAS, France;5. University of Rennes 1, Faculty of Medicine, Rennes, France;6. Department of Regenerative Medicine, Military Institute of Hygiene and Epidemiology (WIHE), Warsaw, Poland;7. The University of Texas, MD Anderson Cancer Center, Department of Genetics, Houston, TX, USA;1. From the Département de Pharmacologie et Physiologie, Faculté de Médecine, Centre de recherche de l''Institut de Cardiologie de Montréal, Université de Montréal, Montréal, Québec H3C 3J7, Canada;1. CINIBA, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, La Plata, Argentina;2. Cátedra de Histología y Embriología, Facultad de Ciencias Veterinarias, Universidad Nacional de La Plata, La Plata, Argentina;1. Department of Biochemistry and Molecular Biology, Faculty of Science and Technology, University of the Basque Country (UPV/EHU), 48080 Bilbao, Spain;2. Department of Chemistry and Biochemistry, Queens College of The City University of New York, Flushing, NY 11367-1597, USA;3. Department of Pathology, University of Utah Health Sciences Center, Salt Lake City, Utah 84112;4. Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, California 95064;5. Center for Eukaryotic Gene Regulation, The Pennsylvania State University, University Park, Pennsylvania 16802;6. Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, Pennsylvania 16802;1. National Institute of Materials Physics, Lab. Optical Process in Nanostructured Materials, P.O. Box MG-7, Bucharest R077125, Romania;2. Institut des Matériaux Jean Rouxel, 2 rue de la Houssinière, B.P. 32229, F-44322 Nantes, France |
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| Abstract: | Macrophages play crucial role in tissue homeostasis and the innate and adaptive immune response. Depending on the state of activation macrophages acquire distinct phenotypes that depend on actin, which is regulated by small GTPase RhoA. The naive M0 macrophages are slightly elongated, pro-inflammatory M1 are round and M2 anti-inflammatory macrophages are elongated. We showed previously that interference with RhoA pathway (RhoA deletion or RhoA/ROCK kinase inhibition) disrupted actin, produced extremely elongated (hummingbird) macrophage phenotype and inhibited macrophage movement toward transplanted hearts. The RhoA function depends on the family of guanine-nucleotide exchange factors (GEFs), which catalyze the exchange of GDP for GTP and activate RhoA that reorganizes actin cytoskeleton. Using actin staining, immunostaining, Western blotting, flow cytometry and transmission electron microscopy we studied how a direct inhibition of Rho-GEFs with Rhosin (Rho GEF-binding domain blocker) and Y16 (Rho GEF DH-PH domain blocker) affects M0, M1 and M2 macrophage phenotypes. We also studied how Rho-GEFs inhibition and RhoA deletion affects organization of Golgi complex that is crucial for normal macrophage functions such as phagocytosis, antigen presentation and receptor recycling. We found that GEFs inhibition differently affected M0, M1 and M2 macrophages phenotype and that GEFs inhibition and RhoA deletion both caused changes in the ultrastructure of the Golgi complex. These results suggest that actin/RhoA- dependent shaping of macrophage phenotype has different requirements for activity of RhoA/GEFs pathway in M0, M1 and M2 macrophages, and that RhoA and Rho-GEFs functions are necessary for the maintenance of actin-dependent organization of Golgi complex. |
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| Keywords: | Macrophage Actin Cytoskeleton Golgi complex RhoA |
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