B lymphocyte-derived acetylcholine limits steady-state and emergency hematopoiesis

Abstract

Autonomic nerves control organ function through the sympathetic and parasympathetic branches, which have opposite effects. In the bone marrow, sympathetic (adrenergic) nerves promote hematopoiesis; however, how parasympathetic (cholinergic) signals modulate haematopoiesis is unclear. Here we show that B lymphocytes were an important source of acetylcholine, a neurotransmitter of the parasympathetic nervous system which reduced hematopoiesis. Single cell RNA sequencing identified 9 clusters of cells that expressed the acetylcholine receptor Chrna7 in the bone marrow stem cell niche, including endothelial and mesenchymal stromal cells. Deletion of B cell-derived acetylcholine resulted in the differential expression of various genes, including Cxcl12 in LepR + stromal cells. Pharmacologic inhibition of acetylcholine signaling increased the systemic supply of inflammatory myeloid cells in mice and patients with cardiovascular disease.

Differential Regulation of Allergic Airway Inflammation by Acetylcholine

“…Previously, we have identified lung B cells as a significant source of non-neuronal ChAT and thus ACh synthesis in mice ( 4 ). Therefore, in line with previous studies ( 24 , 28 ), it is possible that B cell production of ACh regulates neutrophil trafficking at homeostasis in the lung.…”

The immune system as a system of relations

“…Both are involved in the sleep-wake cycle, but serotonergic pathways control a variety of other processes, including emotional behavior, circadian rhythm, appetite, and many visceral activities such as sexual behavior, and gastrointestinal movements ( 35 ). Likewise, the parasympathetic neurotransmitter acetylcholine was found to be produced by B lymphocytes and to negatively regulate hematopoiesis ( 36 ), by T lymphocytes and to control viral infection ( 37 ), and by type-2 Innate Lymphoid Cells (ILC2) and to promote anti-helminth immunity ( 38 ) ( 39 ).…”

Immune cell cholinergic signaling in adipose thermoregulation and immunometabolism

“…Using various approaches, including multiple reporter mouse lines such as ChAT-eGFP mice, which express enhanced green fluorescence protein (eGFP) under the control of the choline acetyltransferase promoter (Chat, the rate-limiting enzyme for ACh biosynthesis), many studies have now convincingly shown that non-neuronal cells, including various types of immune cells, can synthesize ACh [40,41,[65][66][67][68][69][70][71][72][73][74][75][76][77][78][79][80]. Functionally, murine T cells expressing ChAT can inhibit cytokine release [67].…”

“…ChAT-expressing B cells have been reported to diminish the recruitment of neutrophils in mice, thus regulating local innate immunity [70]. Specifically, ACh released from ChAT + B cells in bone marrow curbs myelopoiesis, and, in mice harboring B cell-specific Chat deletion, increased accumulation of inflammatory myeloid cells has been reported to worsen symptoms of myocardial infarction [80]. Moreover, ChAT expression has been observed in murine macrophages in several studies [70,78]; however, aside from ChAMs being able to regulate beige fat, the physiological function of ChAT in macrophages has not been elucidated.…”