TY - JOUR
T1 - B lymphocyte-derived acetylcholine limits steady-state and emergency hematopoiesis
AU - Schloss, Maximilian J.
AU - Hulsmans, Maarten
AU - Rohde, David
AU - Lee, I. Hsiu
AU - Severe, Nicolas
AU - Foy, Brody H.
AU - Pulous, Fadi E.
AU - Zhang, Shuang
AU - Kokkaliaris, Konstantinos D.
AU - Frodermann, Vanessa
AU - Courties, Gabriel
AU - Yang, Chongbo
AU - Iwamoto, Yoshiko
AU - Knudsen, Anders Steen
AU - McAlpine, Cameron S.
AU - Yamazoe, Masahiro
AU - Schmidt, Stephen P.
AU - Wojtkiewicz, Gregory R.
AU - Masson, Gustavo Santos
AU - Gustafsson, Karin
AU - Capen, Diane
AU - Brown, Dennis
AU - Higgins, John M.
AU - Scadden, David T.
AU - Libby, Peter
AU - Swirski, Filip K.
AU - Naxerova, Kamila
AU - Nahrendorf, Matthias
N1 - Funding Information:
M.N. has received funds or material research support from Alnylam, Biotronik, CSL Behring, GlycoMimetics, GSK, Medtronic, Novartis and Pfizer as well as consulting fees from Biogen, Gimv, IFM Therapeutics, Molecular Imaging, Sigilon and Verseau Therapeutics. The other authors declare no competing interests.
Funding Information:
We thank M. Handley, D. Daly, J. Kauffman, P. Sen, G. Lima, J. Choi and E. Surette of the HSCI-CRM Flow Cytometry Core Facility, Massachusetts General Hospital, for their assistance with cell sorting; the Bioanalytics Core at the Diabetes and Obesity Center, Christina Lee Brown Envirome Institute, University of Louisville, for mass spectrometry analysis; the BPF Next-Gen Sequencing Core Facility at Harvard Medical School for their expertise and instrument availability in support of this work and the Partners Healthcare Research Patient Data Registry group for facilitating the use of their database. We thank K. Joyes for editing the article. Figures were designed using Servier Medical Art (http://www.servier.com ). This work was supported in part by the National Institutes of Health grants HL142494, NS108419, HL139598, HL125428, HL155097, HL149647, HL158040 and T32HL076136 and the MGH Research Scholar program. M.J.S. and D.R. were funded by Deutsche Forschungsgemeinschaft (SCHL 2221/1-1 and RO5071/1-1). M.H. was supported by an American Heart Association Career Development Award (19CDA34490005). C.S.M. was funded by NIH K99HL151750 and a Canadian Institutes of Health Research Banting Fellowship. J.M.H. and B.H.F. were supported by a grant from the One Brave Idea Initiative. G.S.M. was funded by the Fundação Lemann. The University of Louisville Diabetes and Obesity Center was supported by NIH P30 GM127607 and user fees. The Microscopy Core facility of the Massachusetts General Hospital Program in Membrane Biology receives support from Boston Area Diabetes and Endocrinology Research Center grant DK57521 and Center for the Study of Inflammatory Bowel Disease grant DK43351.
Funding Information:
We thank M. Handley, D. Daly, J. Kauffman, P. Sen, G. Lima, J. Choi and E. Surette of the HSCI-CRM Flow Cytometry Core Facility, Massachusetts General Hospital, for their assistance with cell sorting; the Bioanalytics Core at the Diabetes and Obesity Center, Christina Lee Brown Envirome Institute, University of Louisville, for mass spectrometry analysis; the BPF Next-Gen Sequencing Core Facility at Harvard Medical School for their expertise and instrument availability in support of this work and the Partners Healthcare Research Patient Data Registry group for facilitating the use of their database. We thank K. Joyes for editing the article. Figures were designed using Servier Medical Art ( http://www.servier.com ). This work was supported in part by the National Institutes of Health grants HL142494, NS108419, HL139598, HL125428, HL155097, HL149647, HL158040 and T32HL076136 and the MGH Research Scholar program. M.J.S. and D.R. were funded by Deutsche Forschungsgemeinschaft (SCHL 2221/1-1 and RO5071/1-1). M.H. was supported by an American Heart Association Career Development Award (19CDA34490005). C.S.M. was funded by NIH K99HL151750 and a Canadian Institutes of Health Research Banting Fellowship. J.M.H. and B.H.F. were supported by a grant from the One Brave Idea Initiative. G.S.M. was funded by the Fundação Lemann. The University of Louisville Diabetes and Obesity Center was supported by NIH P30 GM127607 and user fees. The Microscopy Core facility of the Massachusetts General Hospital Program in Membrane Biology receives support from Boston Area Diabetes and Endocrinology Research Center grant DK57521 and Center for the Study of Inflammatory Bowel Disease grant DK43351.
Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2022/4
Y1 - 2022/4
N2 - 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 hematopoiesis is unclear. Here, we show that B lymphocytes are an important source of acetylcholine, a neurotransmitter of the parasympathetic nervous system, which reduced hematopoiesis. Single-cell RNA sequencing identified nine clusters of cells that expressed the cholinergic α7 nicotinic receptor (Chrna7) in the bone marrow stem cell niche, including endothelial and mesenchymal stromal cells (MSCs). Deletion of B cell-derived acetylcholine resulted in the differential expression of various genes, including Cxcl12 in leptin receptor+ (LepR+) stromal cells. Pharmacologic inhibition of acetylcholine signaling increased the systemic supply of inflammatory myeloid cells in mice and humans with cardiovascular disease.
AB - 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 hematopoiesis is unclear. Here, we show that B lymphocytes are an important source of acetylcholine, a neurotransmitter of the parasympathetic nervous system, which reduced hematopoiesis. Single-cell RNA sequencing identified nine clusters of cells that expressed the cholinergic α7 nicotinic receptor (Chrna7) in the bone marrow stem cell niche, including endothelial and mesenchymal stromal cells (MSCs). Deletion of B cell-derived acetylcholine resulted in the differential expression of various genes, including Cxcl12 in leptin receptor+ (LepR+) stromal cells. Pharmacologic inhibition of acetylcholine signaling increased the systemic supply of inflammatory myeloid cells in mice and humans with cardiovascular disease.
UR - http://www.scopus.com/inward/record.url?scp=85127260395&partnerID=8YFLogxK
U2 - 10.1038/s41590-022-01165-7
DO - 10.1038/s41590-022-01165-7
M3 - Article
C2 - 35352063
AN - SCOPUS:85127260395
SN - 1529-2908
VL - 23
SP - 605
EP - 618
JO - Nature Immunology
JF - Nature Immunology
IS - 4
ER -