Anti‐inflammatory effects of α7‐nicotinic ACh receptors are exerted through interactions with adenylyl cyclase‐6

Background and Purpose Nicotinic ACh receptors containing the α7 sub‐unit (α7‐nAChRs) suppress inflammation through a wide range of pathways in immune cells. These receptors are thus potentially involved in a number of inflammatory diseases. However, the detailed mechanisms underlying the anti‐inflammatory effects of α7‐nAChRs remain to be described. Experimental Approach Anti‐inflammatory effects of α7‐nAChR agonists were assessed in both murine macrophages (RAW 264.7) and bone marrow‐derived macrophages (BMDM), stimulated with LPS, using immunoblotting, RT‐PCR and luciferase reporter assays. The role of adenylyl cyclase‐6 in the degradation of Toll‐like receptor 4 (TLR4) following endocytosis, was explored via overexpression and knockdown. A mouse model of chronic obstructive pulmonary disease (COPD) induced by porcine pancreatic elastase was used to confirm key findings. Results Anti‐inflammatory effects of α7‐nAChRs were largely dependent on adenylyl cyclase‐6 activation, as knockdown of adenylyl cyclase‐6 considerably reduced the effects of α7‐nAChR agonists while adenylyl cyclase‐6 overexpression promoted them. We found that α7‐nAChRs and adenylyl cyclase‐6 are co‐localized in lipid rafts of macrophages and directly interact. Activation of adenylyl cyclase‐6 led to increased degradation of TLR4. Administration of the α7‐nAChR agonist PNU‐282987 attenuated pathological and inflammatory end points in a mouse model of COPD. Conclusion and Implications The α7‐nAChRs inhibit inflammation through activating adenylyl cyclase‐6 and promoting degradation of TLR4. The use of α7‐nAChR agonists may represent a novel therapeutic approach for treating COPD and possibly other inflammatory diseases.