Back to Search
Start Over
Anti-inflammatory effects of α7-nicotinic ACh receptors are exerted through interactions with adenylyl cyclase-6.
- Source :
-
British Journal of Pharmacology . Jun2021, Vol. 178 Issue 11, p2324-2338. 15p. 1 Black and White Photograph, 1 Diagram, 5 Graphs. - Publication Year :
- 2021
-
Abstract
- <bold>Background and Purpose: </bold>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.<bold>Experimental Approach: </bold>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.<bold>Results: </bold>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.<bold>Conclusion and Implications: </bold>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. [ABSTRACT FROM AUTHOR]
- Subjects :
- *LIPID rafts
*LABORATORY mice
*OBSTRUCTIVE lung diseases
*TOLL-like receptors
*ELASTASES
*NICOTINIC agonists
*RESEARCH
*CHOLINERGIC receptors
*ANTI-inflammatory agents
*ANIMAL experimentation
*RESEARCH methodology
*SWINE
*MEDICAL cooperation
*EVALUATION research
*COMPARATIVE studies
*MICE
*PHARMACODYNAMICS
Subjects
Details
- Language :
- English
- ISSN :
- 00071188
- Volume :
- 178
- Issue :
- 11
- Database :
- Academic Search Index
- Journal :
- British Journal of Pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 150293428
- Full Text :
- https://doi.org/10.1111/bph.15412