title: Neuroendocrine signaling via the serotonin transporter regulates clearance of apoptotic cells.
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.
authors.affiliation: COPD Center, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: COPD Center, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045.
authors.forename: Jenna M
authors.initials: JM
authors.lastname: Doe
authors.affiliation: COPD Center, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Horstmann
authors.affiliation: Pediatric Airway Research Center, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045.
authors.forename: Shama
authors.initials: S
authors.lastname: Ahmad
authors.affiliation: Pediatric Airway Research Center, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045.
authors.forename: Aftab
authors.initials: A
authors.lastname: Ahmad
authors.affiliation: Division of Health Care Policy and Research, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045.
authors.forename: Sung-Joon
authors.initials: SJ
authors.lastname: Min
authors.affiliation: Department of Pediatrics, Division of Cell Biology, National Jewish Health, Denver, Colorado 80206.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Reynolds
authors.affiliation: COPD Center, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045.
authors.forename: Saritha
authors.initials: S
authors.lastname: Suram
authors.affiliation: COPD Center, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045.
authors.forename: Jeanette
authors.initials: J
authors.lastname: Gaydos
authors.affiliation: COPD Center, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045.
authors.forename: Ellen L
authors.initials: EL
authors.lastname: Burnham
authors.affiliation: COPD Center, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045. Electronic address: Bill.Vandivier@ucdenver.edu.
authors.forename: R William
authors.initials: RW
authors.lastname: Vandivier
mesh_terms: D000818:Animals; D017209:Apoptosis; D001327:Autoimmune Diseases / Q000378:metabolism; D001692:Biological Transport; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D010587:Phagocytosis; D010766:Phosphorylation; D060888:Real-Time Polymerase Chain Reaction; D012701:Serotonin / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*; D015398:Signal Transduction; D013950:Thymus Gland / Q000166:cytology; D054460:rho-Associated Kinases / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D050486:Serotonin Plasma Membrane Transport Proteins; D012701:Serotonin; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein
keywords: Autoimmune Diseases; Efferocytosis; Inflammation; Lung; Phagocytosis; Rho Kinase; RhoA; Serotonin Receptors