Frontiers in Immunology (Apr 2019)
Forebrain Cholinergic Signaling Regulates Innate Immune Responses and Inflammation
- Kurt R. Lehner,
- Harold A. Silverman,
- Harold A. Silverman,
- Meghan E. Addorisio,
- Ashbeel Roy,
- Ashbeel Roy,
- Mohammed A. Al-Onaizi,
- Mohammed A. Al-Onaizi,
- Yaakov Levine,
- Peder S. Olofsson,
- Peder S. Olofsson,
- Sangeeta S. Chavan,
- Sangeeta S. Chavan,
- Robert Gros,
- Robert Gros,
- Robert Gros,
- Neil M. Nathanson,
- Yousef Al-Abed,
- Yousef Al-Abed,
- Christine N. Metz,
- Christine N. Metz,
- Vania F. Prado,
- Vania F. Prado,
- Vania F. Prado,
- Vania F. Prado,
- Marco A. M. Prado,
- Marco A. M. Prado,
- Marco A. M. Prado,
- Marco A. M. Prado,
- Kevin J. Tracey,
- Kevin J. Tracey,
- Valentin A. Pavlov,
- Valentin A. Pavlov
Affiliations
- Kurt R. Lehner
- Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, United States
- Harold A. Silverman
- Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, United States
- Harold A. Silverman
- Center for Biomedical Science and Bioelectronic Medicine, The Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, United States
- Meghan E. Addorisio
- Center for Biomedical Science and Bioelectronic Medicine, The Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, United States
- Ashbeel Roy
- Schulich School of Medicine and Dentistry, Robarts Research Institute, University of Western Ontario, London, ON, Canada
- Ashbeel Roy
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada
- Mohammed A. Al-Onaizi
- Schulich School of Medicine and Dentistry, Robarts Research Institute, University of Western Ontario, London, ON, Canada
- Mohammed A. Al-Onaizi
- Department of Anatomy, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait
- Yaakov Levine
- SetPoint Medical Corporation, Valencia, CA, United States
- Peder S. Olofsson
- Center for Biomedical Science and Bioelectronic Medicine, The Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, United States
- Peder S. Olofsson
- Department of Medicine, Center for Bioelectronic Medicine, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
- Sangeeta S. Chavan
- Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, United States
- Sangeeta S. Chavan
- Center for Biomedical Science and Bioelectronic Medicine, The Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, United States
- Robert Gros
- Schulich School of Medicine and Dentistry, Robarts Research Institute, University of Western Ontario, London, ON, Canada
- Robert Gros
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada
- Robert Gros
- Department of Medicine, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada
- Neil M. Nathanson
- Department of Pharmacology, University of Washington, Seattle, WA, United States
- Yousef Al-Abed
- Center for Biomedical Science and Bioelectronic Medicine, The Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, United States
- Yousef Al-Abed
- 0Department of Medicinal Chemistry, Center for Molecular Innovation, The Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, United States
- Christine N. Metz
- Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, United States
- Christine N. Metz
- Center for Biomedical Science and Bioelectronic Medicine, The Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, United States
- Vania F. Prado
- Schulich School of Medicine and Dentistry, Robarts Research Institute, University of Western Ontario, London, ON, Canada
- Vania F. Prado
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada
- Vania F. Prado
- 1Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada
- Vania F. Prado
- 2Graduate Program in Neuroscience, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada
- Marco A. M. Prado
- Schulich School of Medicine and Dentistry, Robarts Research Institute, University of Western Ontario, London, ON, Canada
- Marco A. M. Prado
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada
- Marco A. M. Prado
- 1Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada
- Marco A. M. Prado
- 2Graduate Program in Neuroscience, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada
- Kevin J. Tracey
- Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, United States
- Kevin J. Tracey
- Center for Biomedical Science and Bioelectronic Medicine, The Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, United States
- Valentin A. Pavlov
- Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, United States
- Valentin A. Pavlov
- Center for Biomedical Science and Bioelectronic Medicine, The Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, United States
- DOI
- https://doi.org/10.3389/fimmu.2019.00585
- Journal volume & issue
-
Vol. 10
Abstract
The brain regulates physiological functions integral to survival. However, the insight into brain neuronal regulation of peripheral immune function and the neuromediator systems and pathways involved remains limited. Here, utilizing selective genetic and pharmacological approaches, we studied the role of forebrain cholinergic signaling in the regulation of peripheral immune function and inflammation. Forebrain-selective genetic ablation of acetylcholine release and vagotomy abolished the suppression of serum TNF by the centrally-acting cholinergic drug galantamine in murine endotoxemia. Selective stimulation of acetylcholine action on the M1 muscarinic acetylcholine receptor (M1 mAChR) by central administration of the positive allosteric modulator benzyl quinolone carboxylic acid (BQCA) suppressed serum TNF (TNFα) levels in murine endotoxemia. This effect was recapitulated by peripheral administration of the compound. BQCA also improved survival in murine endotoxemia and these effects were abolished in M1 mAChR knockout (KO) mice. Selective optogenetic stimulation of basal forebrain cholinergic neurons innervating brain regions with abundant M1 mAChR localization reduced serum TNF in endotoxemic mice. These findings reveal that forebrain cholinergic neurons regulate innate immune responses and inflammation, suggesting the possibility that in diseases associated with cholinergic dysfunction, including Alzheimer's disease this anti-inflammatory regulation can be impaired. These results also suggest novel anti-inflammatory approaches based on targeting forebrain cholinergic signaling in sepsis and other disorders characterized by immune dysregulation.
Keywords
