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

Abstract

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.

The selective alpha7 nicotinic acetylcholine receptor agonist AR-R17779 does not affect ischemia–reperfusion brain injury in mice

“…We and others have demonstrated an immune modulating effect of the α7nAChR in the periphery, using both genetic models [ 17 , 46–48 ] and pharmacological tools that stimulate the α7nAChR such as AZ6983, AR-R17779 or PNU-282987 [ 16 , 29 , 49 , 50 ]. This effect is predominantly mediated via α7nAChR expressed in monocytes/macrophages.…”

Nicotinic Acetylcholine Receptors in the Respiratory Tract

“…Twenty years ago, the α7 nAChR had already been identified as playing a critical role in the cholinergic anti-inflammatory pathway and as being involved in anti-inflammatory effects [ 44 ]. A recent study revealed that α7 nAChR acts via an activation of adenylyl cyclase 6 and a lipid raft-mediated endocytosis of TLR4 in a COPD mouse model and proposed the use of α7 agonists as a novel approach for COPD treatment [ 45 ]. In line with this, another study revealed that IL6 and NO levels were increased in the blood plasma of COPD patients with peripheral blood mononuclear cells and that these levels were associated with impaired lung function.…”

Photoactivated adenylyl cyclases attenuate sepsis-induced cardiomyopathy by suppressing macrophage-mediated inflammation

“…The generation of cAMP is catalyzed by adenylyl cyclase (AC), a superfamily of 10 protein isoforms with disparate localization in different cells ( 9 ). cAMP has been shown to perform diverse functions in macrophages, such as inhibition of phagocytosis, microbes killing, and the expression of proinflammatory cytokines ( 10 – 13 ). The work from our team showed that AC6 dampens macrophage-mediated inflammation by endocytosis of TLR4 to the lipid-raft mediated pathway leading to its degradation ( 12 ).…”