Document Type

Article

Publication Date

2-18-2021

Abstract

Background and purpose

Alpha 7 nicotinic acetylcholine receptors (CHRNA7) suppress inflammation through diverse pathways in immune cells, so is potentially involved in a number of inflammatory diseases. However, the detailed mechanisms underlying CHRNA7’s anti‐inflammatory effects remain elusive.

Experimental approach

The anti‐inflammatory effects of CHRNA7 agonists in both murine macrophages (RAW 264.7) and bone marrow‐derived macrophages (BMDM) stimulated with LPS were examined. The role of adenylyl cyclase 6 (AC6) in Toll‐like Receptor 4 (TLR4) degradation was explored via overexpression and knockdown. A mouse model of chronic obstructive pulmonary disease was used to confirm key findings.

Results

Anti‐inflammatory effects of CHRNA7 were largely dependent on AC6 activation, as knockdown of AC6 considerably abnegated the effects of CHRNA7 agonists while AC6 overexpression promoted them. We found that CHRNA7 and AC6 are co‐localized in lipid rafts of macrophages and directly interact. Activation of AC6 led to the promotion of TLR4 degradation. Administration of CHRNA7 agonist PNU‐282987 attenuated pathological and inflammatory end points in a mouse model of chronic obstructive pulmonary disease (COPD).

Conclusion and implications

CHRNA7 inhibits inflammation through activating AC6 and promoting degradation of TLR4. The use of CHRNA7 agonists may represent a novel therapeutic approach for treating COPD and likely other inflammatory diseases.

Comments

This is the accepted version of the following article:

Zhu, S, Huang, S, Xia, G, et al. Anti‐inflammatory effects of alpha 7 nicotinic acetylcholine receptors through interacting with adenylyl cyclase 6. Br J Pharmacol. 2021.

which has been published in final form at https://doi.org/10.1111/bph.15412. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.

Copyright

British Pharmacological Society

Available for download on Friday, February 18, 2022

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