Physiological role of olfactory receptors in alveolar macrophages

Abstract

New therapeutic approaches are required to decelerate the progression of COPD and severe asthma with non-type2 inflammation. Alveolar macrophages (AM) might be suitable targets because of their key role in the pathophysiologies. Pre-clinical studies and clinical trials currently investigate the potential of ectopic olfactory receptors (OR), the largest subgroup of G-protein coupled receptors, as therapeutic targets in several non-respiratory diseases. Pre-clinical data about their potential in obstructive lung diseases are lacking.

Method: OR2AT4 and OR1A1/OR1A2 are suitable candidates and their synthetic agonists Sandalore or (‑)Citronellal, respectively, might repair dysregulated molecular processes in COPD or asthma like calcium signaling and phagocytosis of alveolar macrophages.

AM were isolated from the bronchoalveolar lavage (BAL) of patients with (suspected) COPD or asthma. Both, OR2AT4 and OR1A2 proteins were detected by western blot and in the membrane of the AM by immunocytochemical staining. Their mRNAs were not detected by well controlled RT-PCR. Sandalore and Citronellal, both induced a concentration-dependent and transient increase of intracellular calcium. For Sandalore this was blocked by Oxyphenylon (OR2AT4 blocker), MDL12330A (adenylate cyclase blocker) and withdrawal of extracellular calcium with EGTA suggesting the involvement of the cAMP-dependent pathway. The phagocytotic activity was reduced by both agonists.

AM functionally express OR2AT4 and OR1A2 but do not perform de-novo synthesis. Both ORs interfere with the calcium balance of the cells and inhibit phagocytosis. This is first indication for OR2AT4 and OR1A2 as therapeutic targets in obstructive lung diseases.