Serotonin activates murine alveolar macrophages through 5-HT2C receptors

Mikulski Z, Zaslona Z, Cakarova L, Hartmann P, Wilhelm J, Tecott LH, Lohmeyer J, Kummer W. Serotonin activates murine alveolar macrophages through 5-HT2C receptors. Am J Physiol Lung Cell Mol Physiol 299: L272-L280, 2010. First published May 21, 2010; doi:10.1152/ajplung.00032.2010.-Serotonin (5-HT), known as neuromodulator, regulates immune responses and inflammatory cascades. The expression and function of 5-HT receptors on alveolar macrophages (AM), which are the major fraction of pulmonary immune cells, remain elusive. Therefore, we determined the expression of 5-HT type 2 receptors and investigated the effects evoked by stimulation with 5-HT in AM compared with alveolar epithelial cells (AEC). Quantitative PCR (qPCR) analysis revealed expression of the receptors 5-HT2A and 5-HT2B in AEC and of 5-HT2C in AM. In AM, 5-HT (10(-5) M) induced a rise in intracellular calcium concentration ([Ca2+](i)) that was initiated by release of Ca2+ from intracellular stores and depended on extracellular Ca2+ in a sustained phase. This 5-HT-induced increase in [Ca2+](i) was not observed in AM treated with the 5-HT2C-selective inhibitor RS-102221 and in AM derived from 5-HT2C-deficient mice. AM stimulated with 5-HT (10(-5) M) showed increased expression of CCL2 (MCP-1) mRNA as assayed by qPCR at 4 h and augmented production of CCL2 protein as determined by dot-blot assay and ELISA at 24 h. Notably, in 5-HT2C-deficient AM, CCL2 production was not induced by 5-HT treatment. Moreover, transcriptional responses to 5-HT exposure assayed by microarray experiments were only observed in AM from wild-type animals and not in AM derived from 5-HT2C-deficient mice. Taken together, these data demonstrate the presence of functional 5-HT2C receptors on AM and suggest a role of 5-HT as novel modulator of AM function. These effects are exclusively driven by the 5-HT2C receptor, thereby providing the potential for selective intervention.