Simeng Zhu1, Shiqian Huang1,2, Guofang Xia1, Jin Wu3, Yan Shen4, Ying Wang2, Rennolds S Ostrom5, Ailian Du6, Chengxing Shen1, Congfeng Xu1,2. 1. Department of Cardiology, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai Jiaotong University School of Medicine (SJTUSM), Shanghai, China. 2. Shanghai Institute of Immunology, Institutes of Medical Sciences, Shanghai Jiaotong University School of Medicine, Shanghai, China. 3. Shanghai Institute for Pediatric Research, Shanghai Jiaotong University School of Medicine, Shanghai, China. 4. Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. 5. Department of Biomedical and Pharmaceutical Sciences, Chapman University, Irvine, California, United States. 6. Department of Neurology, Tongren Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
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.
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.
Authors: Katrina F Ostrom; Justin E LaVigne; Tarsis F Brust; Roland Seifert; Carmen W Dessauer; Val J Watts; Rennolds S Ostrom Journal: Physiol Rev Date: 2021-10-26 Impact factor: 37.312
Authors: Maria E Hammarlund; Vladimer Darsalia; Filip Mjörnstedt; Bagmi Pattanaik; Carina Mallard; Eridan Rocha-Ferreira; Cesare Patrone; Maria E Johansson Journal: Biosci Rep Date: 2021-06-25 Impact factor: 3.840