Function of the olfactory receptor OR2AT4 in alveolar macrophages

New therapeutic options are required to stop the disease progression of COPD and severe asthma, particularly in phenotypes with neutrophilic inflammation. Alveolar macrophages (AMs) might be a suitable target cell as they play a central role in these obstructive lung disease phenotypes. The understanding of olfactory receptors (ORs), G-protein-coupled receptors that are expressed on many cell types beyond the olfactory epithelium is still in its infancy. Recent research has suggested them as molecular therapeutic targets in several diseases including NSCLC. Moreover, Ca-dependent signaling and phagocytosis in AM are dysregulated in obstructive lung diseases.

In this project we investigate human primary AM for expression of ORs and try to understand if OR activity might be linked to the molecular pathology of obstructive lung diseases. This would enable us to decipher its possible role as therapeutic targets.

AM were isolated from the broncho-alveolar lavage of patients. In this early phase of the project, patients were not classified by disease. The receptor OR2AT4 was detected on AM by western blot. Immunocytochemical staining revealed OR2AT4 localization in the plasma membrane. OR2AT4 mRNA was not detected by RT-PCR. Stimulation of AM with the OR2AT4 ligand Sandalore increased intracellular calcium levels in a concentration-dependent manner. Oxyphenylon, a competitive antagonist of OR2AT4, blocked the Sandalore-induced increase in intracellular calcium concentration. Sandalore partially blocked the phagocytosis activity of AM at high concentrations.

AM carry functional OR2AT4 but do not perform OR2AT4 de-novo synthesis. OR2AT4 is linked directly to Ca-dependent signaling pathways. OR2AT4 activity interferes with the phagocytosis activity of AM. These data provide first indication for OR2AT4 as a molecular therapeutic target in obstructive lung diseases.