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Acetylcholine Derived From B Cells May Protect Against Cardiovascular Disease

Key findings

  • This study investigated how peripheral cholinergic signaling affects the production of leukocytes in bone marrow
  • Acetylcholine esterase inhibition, which augments acetylcholine levels, reduced hematopoiesis in humans and mice
  • Unexpectedly, B cells were the primary source of acetylcholine in bone marrow, and B cell–derived acetylcholine modulated steady-state hematopoiesis
  • Acetylcholine influenced hematopoiesis through signaling to stromal niche cells via Chrna7, a receptor for acetylcholine
  • B cell–derived acetylcholine protected against atherosclerosis and post–myocardial infarction heart failure in mice by regulating immune cell production

The autonomic nervous system has a marked influence on cardiovascular diseases (CVD), including hypertension, heart failure, and arrhythmias, because of its role in maintaining sympathetic tone. That can lead to vasoconstriction, fluid retention, cardiac hypertrophy, and heart failure.

The parasympathetic nerves counter that response, mainly through the neurotransmitter acetylcholine. To better understand this protective effect, Maximilian J. Schloss, MD, former postdoctoral fellow at the Center for Systems Biology in the Mass General Research Institute, Matthias Nahrendorf, MD, PhD, director of the Mouse Imaging Program at the center, and colleagues studied acetylcholine in the bone marrow.

As expected, acetylcholine reduced levels of inflammatory leukocytes that can harm arteries and the heart. But in Nature Immunologythe team also reports a surprising result that might lead to new therapeutic approaches: Acetylcholine in the bone marrow was produced by B cells, not nerve fibers.

Key Initial Findings

  • Acetylcholine esterase inhibitors, which augment acetylcholine levels, were associated with decreased numbers of leukocytes in humans and mice
  • In mice, B cells positive for choline acetyltransferase (Chat), an enzyme essential for the synthesis of acetylcholine, were the primary source of acetylcholine in the bone marrow
  • In mice that had B cell–specific deletion of Chat, the number of leukocytes and the numbers of hematopoietic stem and progenitor cells were higher than in control mice, suggesting that B cell–derived acetylcholine regulates steady-state hematopoiesis
  • Other knockout mouse experiments indicated stromal cells in the hematopoietic niche of bone marrow sense acetylcholine via Chrna7 (a receptor for acetylcholine), and B cell–derived acetylcholine can influence the phenotypes of various hematopoietic niche cells, ultimately reducing steady-state hematopoiesis

Therapeutic Relevance

The effect of cholinergic signaling on hematopoiesis seems to represent a therapeutic opportunity:

  • When either chronic CVD (atherosclerosis) or acute CVD (myocardial infarction [MI]) was induced in mice lacking Chat in B cells, the animals had more cardiovascular inflammation and worse outcomes than control mice
  • When MI was induced in normal inbred laboratory mice, those treated with an acetylcholine esterase inhibitor showed fewer inflammatory myeloid cells and less collagen deposition than saline-treated mice
  • In a retrospective analysis, 70 patients who suffered MI while they were taking donepezil, an acetylcholine esterase inhibitor, for Alzheimer's disease showed less increase in harmful leukocytes than 70 matched patients who had not been using donepezil

Pharmacologic targets associated with cholinergic signaling may be relevant to any leukocyte-related condition, inflammatory or not. In fact, since B cell–derived acetylcholine altered the proliferation of hematopoietic progenitors, the results of this study may find application in bone marrow transplantation.

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Researchers from the Center for Systems Biology at Massachusetts General Hospital and colleagues address how three heart disease milestones—hypertension, atherosclerosis and myocardial infarction—impair the bone marrow's vascular health, suggesting a new direction for development of cardiovascular disease therapies.