The serotonin receptor 5’HTR2c regulates alveolar macrophage responses post-helminth infection 2257539

Abstract Introduction Alveolar macrophages (AMs) are highly specialized cells that have long been recognized for their ability to regulate lung homeostasis. Additionally, it is well appreciated that AMs perform important antihelminth functions and are required to promote wound healing responses following the passage of larvae through the lung. Despite these advances, the molecular features of AMs that allow them to perform these tissue-specific functions remain to be fully understood. Recent RNAseq data has revealed that AMs uniquely express the serotonin receptor 5’HTR2c, the only immune cell population to do so. Knowing that serotonin is released at the site of injury by activated platelets, we hypothesized that 5’HTR2c regulates the activation of AMs in the context of helminth-induced damage. Methods To test this, we employed the hookworm Nippostrongylus brasiliensis (Nb), that promotes severe lung pathology and the robust activation of AMs. Following infection, we observed that mice lacking expression of 5’HTR2c on AMs (HTR2c flox x CD11c-Cre mice) failed to properly resolve Nb-induced damage as highlighted by an accumulation of red blood cells in the bronchoalveolar spaces of the lungs. Results When investigating the mechanisms dictating these phenotypes, we identified that serotonin is a potent initiator of calcium responses in AMs as measured using the calcium indicator dye Fura2. Further, we determined that serotonin-induced calcium signals were 5’HTR2c-dependent, despite the fact that AMs also express the 5’HTR2b receptor. Conclusion Collectively, these data suggest that expression of the 5’HTR2c receptor by AMs allow them to properly clear debris and restore lung homeostasis following helminth-induced injury. Our ongoing studies are working to better understand the molecular mechanism dictating these changes and the long-term effects of targeting this pathway in the context of helminth-induced inflammation. Funding Source N/A Topic Categories Mucosal and Regional Immunology (MUC)