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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Doe, Jenna M. Burnham, Ellen L. Suram, Saritha Vandivier, R. William Ahmad, Shama Horstmann, Sarah A. Min, Sung-joon Reynolds, Paul R. Ahmad, Aftab Gaydos, Jeanette Tanaka, Takeshi |
| Description | Author Affiliation: Tanaka T ( From the COPD Center, Division of Pulmonary Sciences and Critical Care Medicine.) |
| Abstract | Serotonin (5-hydroxytryptamine; 5-HT) is a CNS neurotransmitter increasingly recognized to exert immunomodulatory effects outside the CNS that contribute to the pathogenesis of autoimmune and chronic inflammatory diseases. 5-HT signals to activate the RhoA/Rho kinase (ROCK) pathway, a pathway known for its ability to regulate phagocytosis. The clearance of apoptotic cells (i.e. efferocytosis) is a key modulator of the immune response that is inhibited by the RhoA/ROCK pathway. Because efferocytosis is defective in many of the same illnesses where 5-HT has been implicated in disease pathogenesis, we hypothesized that 5-HT would suppress efferocytosis via activation of RhoA/ROCK. The effect of 5-HT on efferocytosis was examined in murine peritoneal and human alveolar macrophages, and its mechanisms were investigated using pharmacologic blockade and genetic deletion. 5-HT impaired efferocytosis by murine peritoneal macrophages and human alveolar macrophages. 5-HT increased phosphorylation of myosin phosphatase subunit 1 (Mypt-1), a known ROCK target, and inhibitors of RhoA and ROCK reversed the suppressive effect of 5-HT on efferocytosis. Peritoneal macrophages expressed the 5-HT transporter and 5-HT receptors (R) 2a, 2b, but not 2c. Inhibition of 5-HTR2a and 5-HTR2b had no effect on efferocytosis, but blockade of the 5-HT transporter prevented 5-HT-impaired efferocytosis. Genetic deletion of the 5-HT transporter inhibited 5-HT uptake into peritoneal macrophages, prevented 5-HT-induced phosphorylation of Mypt-1, reversed the inhibitory effect of 5-HT on efferocytosis, and decreased cellular peritoneal inflammation. These results suggest a novel mechanism by which 5-HT might disrupt efferocytosis and contribute to the pathogenesis of autoimmune and chronic inflammatory diseases. |
| ISSN | 00219258 |
| e-ISSN | 1083351X |
| Journal | Journal of Biological Chemistry |
| Issue Number | 15 |
| Volume Number | 289 |
| Language | English |
| Publisher | American Society for Biochemistry and Molecular Biology (United States) |
| Publisher Date | 2014-04-11 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Apoptosis Phagocytosis Serotonin Plasma Membrane Transport Proteins Metabolism Serotonin Signal Transduction Animals Autoimmune Diseases Biological Transport Cells, Cultured Gene Expression Regulation Inflammation Macrophages, Alveolar Cytology Mice Mice, Inbred C57BL Mice, Knockout Models, Biological Phosphorylation Real-Time Polymerase Chain Reaction Thymus Gland Rho-Associated Kinases RhoA GTP-Binding Protein Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Biochemistry Molecular Biology |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cell Biology Biochemistry Molecular Biology |
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