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Published on: June 8, 2012
Serotonin activates murine alveolar macrophages through 5-HT2C receptors
Zbigniew Mikulski1, Zbigniew Zaslona, Lidija Cakarova
1Institute of Anatomy and Cell Biology, Universities of Giessen and Marburg Lung Center, Germany.
Abstract:
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-HT(2A) and 5-HT(2B) in AEC and of 5-HT(2C) in AM. In AM, 5-HT (10(-5) M) induced a rise in intracellular calcium concentration ([Ca(2+)](i)) that was initiated by release of Ca(2+) from intracellular stores and depended on extracellular Ca(2+) in a sustained phase. This 5-HT-induced increase in [Ca(2+)](i) was not observed in AM treated with the 5-HT(2C)-selective inhibitor RS-102221 and in AM derived from 5-HT(2C)-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-HT(2C)-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-HT(2C)-deficient mice. Taken together, these data demonstrate the presence of functional 5-HT(2C) receptors on AM and suggest a role of 5-HT as novel modulator of AM function. These effects are exclusively driven by the 5-HT(2C) receptor, thereby providing the potential for selective intervention.
Insights
Serotonin (5-HT) activates functional 5-HT2C receptors on alveolar macrophages (AM), modulating immune responses. This discovery offers potential for targeted therapies by selectively intervening with 5-HT2C receptor signaling in lung immunity.
Area of Science:
- Pulmonary immunology
- Neuroimmunology
- Cellular signaling
Background:
- Serotonin (5-HT) is a neuromodulator regulating immune responses.
- The role of 5-HT receptors on alveolar macrophages (AM) in lung immunity is largely unknown.
- Alveolar macrophages are key immune cells in the pulmonary system.
Purpose of the Study:
- To investigate the expression and function of 5-HT type 2 receptors on AM.
- To determine the effects of 5-HT stimulation on AM compared to alveolar epithelial cells (AEC).
- To elucidate the specific 5-HT receptor subtype involved in AM responses.
Main Methods:
- Quantitative PCR (qPCR) to detect receptor expression.
- Measurement of intracellular calcium concentration ([Ca(2+)](i)) changes.
- Use of 5-HT2C-selective inhibitors and 5-HT2C-deficient mice.
- Assays for CCL2 (MCP-1) mRNA and protein expression (microarray, dot-blot, ELISA).
Main Results:
- 5-HT2C receptors were identified on AM, while 5-HT2A and 5-HT2B were found on AEC.
- 5-HT stimulation increased intracellular calcium in AM via 5-HT2C receptors.
- 5-HT induced CCL2 (MCP-1) mRNA and protein production in AM through 5-HT2C receptors.
- Transcriptional responses to 5-HT were dependent on functional 5-HT2C receptors.
Conclusions:
- Functional 5-HT2C receptors are present on alveolar macrophages.
- Serotonin acts as a novel modulator of AM function, specifically through the 5-HT2C receptor.
- This finding presents opportunities for selective therapeutic interventions targeting lung immune responses.
