Neuroendocrine Signaling Via the Serotonin Transporter Regulates Clearance of Apoptotic Cells |
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Authors: | Takeshi Tanaka Jenna M Doe Sarah A Horstmann Shama Ahmad Aftab Ahmad Sung-Joon Min Paul R Reynolds Saritha Suram Jeanette Gaydos Ellen L Burnham R William Vandivier |
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Institution: | From the ‡COPD Center, Division of Pulmonary Sciences and Critical Care Medicine.;§Pediatric Airway Research Center, Department of Pediatrics.;¶Division of Health Care Policy and Research, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045 and ;the ‖Department of Pediatrics, Division of Cell Biology, National Jewish Health, Denver, Colorado 80206 |
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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. |
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Keywords: | Autoimmune Diseases Inflammation Lung Phagocytosis RhoA Efferocytosis Rho Kinase Serotonin Receptors |
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