Alpha-Adrenergic Receptors – Hematopoiesis
Hematopoiesis takes place in specialized structures of the bone marrow (BM) called hematopoietic niches. These structures are composed of stromal cells, blood vessels, hematopoietic cells and sympathetic nerve fibers. The notion that BM is innervated by myelinated and non-myelinated nerve fibers dates back to 1916 (1). However, the first evidences that sympathetic nerve signals may regulate hematopoiesis was published in the nineties (2-5).
These studies, performed in mice, demonstrated that adrenergic signals may modulate regenerative hematopoiesis after syngeneic BM transplantation and rescue hematopoietic progenitors from the toxic effect of myeloablative treatments by activating α1-adrenergic receptors (α-1ARs) possibly expressed on lymphoid precursors. These effects also involved a circadian regulation of the lymphoid /myeloid differentiation ratio of hematopoietic cells progenitors (6).
In BM cultures, norepinephrine (NE) inhibited the growth of granulocytes and macrophages colonies (GM-CFU) and the effect was neutralized by the α1- AR antagonist prazosin (2-4). NE proved also to protect GM-CFU in BM cells expressing high affinity α-1ARs from the toxic effect of carboplatin and the effect was counteracted by low concentrations of prazosin (5). After a decade, additional studies expanded the field and broadened the notion that the sympathetic nervous system (SNS) exerts an important regulatory role in both steady state hematopoiesis as well as in regenerative hematopoiesis.
Adrenergic mechanisms govern the circadian traffic of HSCs and leukocytes in and out the BM by modulating the expression of the chemokine CXCL12 by mesenchymal stromal cells, a phenomenon needed to maintain an efficient hematopoiesis and to patrol the organism against infections (7). Similarly, the SNS proved to be essential in the effect of granulocyte colony stimulating factor (G-CSF) used clinically to mobilize HSCs in transplantation procedures (7).
The important notion that catecholamines secreted by sympathetic nerves in the BM may enhance hematopoiesis was also confirmed at the level of hematopoietic stem cells (HSCs) in both mice and humans (8,9). All together, these findings provided new possible therapeutic approaches to improve the success of HSCs transplantation and partially explained the mechanism underlying the hematopoietic disorders associated with aging and chronic stress.
However, these studies claimed that the sympathetic regulation of hematopoiesis is mediated exclusively by β2-ARs, β3-ARs and even by α-7 nicotinic receptors but no study took in consideration a possible role of α-ARs. This is rather surprising as α-ARs are undoubtedly expressed on BM cells present in the hematopoietic niche. Apart from the original studies describing α1-ARs expression on lymphoid precursors, these adrenoceptors are, for example, expressed by macrophages, a cell type playing an important role in the hematopoietic niche (10).
This exclusion is astonishing because the SNS regulation of hematopoiesis is still far from a complete understanding. For example, the recent reports about the ability of NE to stimulate hematopoiesis state that the effect is mediated by β-ARs but the underlying mechanism and/or the cell type involved in this effect remain unknown. Likewise, the studies about the hematopoietic role of by β-ARs did not shed light on mechanisms regulating the lymphoid vs myeloid differentiation ratio in spite that the early reports showed that α1-ARs were the adrenoceptors apparently doing it (2-5).
Perhaps, the fact that the studies involving β-ARs in the SNS regulation of hematopoiesis have been published in very authoritative journals created a kind of cultural bias similar to the “cultural separation” that once affected the main stream immunologists that did not consider the nervous regulation of the immune system as a serious issue (11).
References
- Drinker, C. K.; Drinker, K. R. A method for maintaining an artificial circulation through the tibia of the dog, with a demonstration of the vasomotor control of the marrow vessels. J. Physiol.1916, 40, 514-521.
- Maestroni, G.J.; Conti, A.; Pedrinis, E. Effect of adrenergic agents on hematopoiesis after syngeneic bone marrow transplantation in mice. 1992, 80(5),1178-82. PMID: 1515638.
- Maestroni, G.J.; Cosentino, M.; Marino, F.; Togni, M.; Conti, A.; Lecchini, S.; Frigo, G. Neural and endogenous catecholamines in the bone marrow. Circadian association of norepinephrine with hematopoiesis? Exp Hematol. 1998, Nov26(12), 1172-7. PMID: 9808057.
- Maestroni, G.J.; Togni, M.; Covacci V. Norepinephrine protects mice from acute lethal doses of carboplatin. Exp Hematol. 1997 Jun 25(6), 491-4. PMID: 9197326.
- Togni, M.; Maestroni,G. Hematopoietic rescue in mice via alpha 1-adrenoceptors on bone marrow B cell precursors. Int J Oncol, 1996, 9(2), 313-318. doi:10.3892/ijo.9.2.313.
- Maestroni, G.J.M. Adrenergic Modulation of Hematopoiesis. J Neuroimmune Pharmacol. 2020, 15(1), 82-92. doi:10.1007/s11481-019-09840-7.
- Hanoun, M.; Maryanovich, M.; Arnal-Estapé, A.; Frenette, P.S. Neural regulation of hematopoiesis, inflammation, and cancer. Neuron. 2015, 86(2), 360-373. doi:10.1016/j.neuron.2015.01.026.
- Lucas, D.; Scheiermann, C.; Chow, A.; Kunisaki, Y.; Bruns, I.; Barrick, C.; Tessarollo, L.; Frenette, P.S. Chemotherapy-induced bone marrow nerve injury impairs hematopoietic regeneration. Nat Med. 2013, Jun;19(6), 695-703. doi: 10.1038/nm.3155.
- Spiegel, A.; Shivtiel, S.; Kalinkovich, A,.; Ludin, A.; Netzer, N.; Goichberg ,P.; Azaria, Y.; Resnick, I.; Hardan, I.; Ben-Hur ,H.; Nagler, A.; Rubinstein, M.; Lapidot T. Catecholaminergic neurotransmitters regulate migration and repopulation of immature human CD34+ cells through Wnt signaling. Nat Immunol. 2007 Oct 8(10), 1123-31. doi: 10.1038/ni1509.
- Pinho, S.; Frenette, P.S. Haematopoietic stem cell activity and interactions with the niche.Nat Rev Mol Cell Biol. 2019, 20(5), 303-320. doi:10.1038/s41580-019-0103-9.
- Maestroni, G. Immunology needs the mind. Nat Immunol. 2004, 5(8), doi:10.1038/ni0804-763.
Author Affiliation
Georges JM Maestroni – Center of Research in Medical Pharmacology, University of Insubria, Varese, Italy. georges.maestroni@tim.it
Cover Image Credit (right panel): Bone marrow histology, by Lorenzo Crumbie, MBBS, BSc; The bony skeleton that supports the human body and facilitates locomotion has an intricate microarchitecture of its own. The cavities created by the trabecular arrangement of the core of the bones are occupied by a mixture of blood cells across a large spectrum of development, and adipocytes. This tissue is known as bone marrow and is responsible for the production of blood cells – a process known as hematopoiesis. Source: https://www.kenhub.com/; url: https://www.kenhub.com/en/library/anatomy/histology-of-bone-marrow
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Alpha-Adrenergic Receptors And Hematopoiesis
Alpha-Adrenergic Receptors – Hematopoiesis
Hematopoiesis takes place in specialized structures of the bone marrow (BM) called hematopoietic niches. These structures are composed of stromal cells, blood vessels, hematopoietic cells and sympathetic nerve fibers. The notion that BM is innervated by myelinated and non-myelinated nerve fibers dates back to 1916 (1). However, the first evidences that sympathetic nerve signals may regulate hematopoiesis was published in the nineties (2-5).
These studies, performed in mice, demonstrated that adrenergic signals may modulate regenerative hematopoiesis after syngeneic BM transplantation and rescue hematopoietic progenitors from the toxic effect of myeloablative treatments by activating α1-adrenergic receptors (α-1ARs) possibly expressed on lymphoid precursors. These effects also involved a circadian regulation of the lymphoid /myeloid differentiation ratio of hematopoietic cells progenitors (6).
In BM cultures, norepinephrine (NE) inhibited the growth of granulocytes and macrophages colonies (GM-CFU) and the effect was neutralized by the α1- AR antagonist prazosin (2-4). NE proved also to protect GM-CFU in BM cells expressing high affinity α-1ARs from the toxic effect of carboplatin and the effect was counteracted by low concentrations of prazosin (5). After a decade, additional studies expanded the field and broadened the notion that the sympathetic nervous system (SNS) exerts an important regulatory role in both steady state hematopoiesis as well as in regenerative hematopoiesis.
Adrenergic mechanisms govern the circadian traffic of HSCs and leukocytes in and out the BM by modulating the expression of the chemokine CXCL12 by mesenchymal stromal cells, a phenomenon needed to maintain an efficient hematopoiesis and to patrol the organism against infections (7). Similarly, the SNS proved to be essential in the effect of granulocyte colony stimulating factor (G-CSF) used clinically to mobilize HSCs in transplantation procedures (7).
The important notion that catecholamines secreted by sympathetic nerves in the BM may enhance hematopoiesis was also confirmed at the level of hematopoietic stem cells (HSCs) in both mice and humans (8,9). All together, these findings provided new possible therapeutic approaches to improve the success of HSCs transplantation and partially explained the mechanism underlying the hematopoietic disorders associated with aging and chronic stress.
However, these studies claimed that the sympathetic regulation of hematopoiesis is mediated exclusively by β2-ARs, β3-ARs and even by α-7 nicotinic receptors but no study took in consideration a possible role of α-ARs. This is rather surprising as α-ARs are undoubtedly expressed on BM cells present in the hematopoietic niche. Apart from the original studies describing α1-ARs expression on lymphoid precursors, these adrenoceptors are, for example, expressed by macrophages, a cell type playing an important role in the hematopoietic niche (10).
This exclusion is astonishing because the SNS regulation of hematopoiesis is still far from a complete understanding. For example, the recent reports about the ability of NE to stimulate hematopoiesis state that the effect is mediated by β-ARs but the underlying mechanism and/or the cell type involved in this effect remain unknown. Likewise, the studies about the hematopoietic role of by β-ARs did not shed light on mechanisms regulating the lymphoid vs myeloid differentiation ratio in spite that the early reports showed that α1-ARs were the adrenoceptors apparently doing it (2-5).
Perhaps, the fact that the studies involving β-ARs in the SNS regulation of hematopoiesis have been published in very authoritative journals created a kind of cultural bias similar to the “cultural separation” that once affected the main stream immunologists that did not consider the nervous regulation of the immune system as a serious issue (11).
References
Author Affiliation
Georges JM Maestroni – Center of Research in Medical Pharmacology, University of Insubria, Varese, Italy. georges.maestroni@tim.it
Cover Image Credit (right panel): Bone marrow histology, by Lorenzo Crumbie, MBBS, BSc; The bony skeleton that supports the human body and facilitates locomotion has an intricate microarchitecture of its own. The cavities created by the trabecular arrangement of the core of the bones are occupied by a mixture of blood cells across a large spectrum of development, and adipocytes. This tissue is known as bone marrow and is responsible for the production of blood cells – a process known as hematopoiesis. Source: https://www.kenhub.com/; url: https://www.kenhub.com/en/library/anatomy/histology-of-bone-marrow
Related stories you may like:
Stress and Hematopoiesis: Activation of Hematopoietic stem cells and Neutrophil and Monocyte Production
Tachykinins, Bone Marrow and Hematopoiesis
Circadian oscillations in leukocyte migration and their control by sympathetic nerves
Autonomic Nervous System Control of Leukocyte Distribution: Physiology and Implications
Sympathetic Nerves via β2-adrenoceptor Signaling Generate Circadian Rhythms and Govern Lymphocyte Recirculation in Lymph Nodes