Central autonomic control of the bone marrow: Multisynaptic tract tracing by recombinant pseudorabies virus

Dénes, Ádám; Boldogköi, Zsolt; Uhereczky, Gabriella; Hornyák, Ákos; Rusvai, Miklós; Palkovits, Miklós; Kovács, Krisztina

doi:10.1016/j.neuroscience.2005.03.060

Cited by 121 publications

(86 citation statements)

References 76 publications

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“…S1A). To map the central autonomic pathway controlling these neurons, retrograde transneuronal tracing was carried out using a recombinant pseudorabies virus inoculated into the distal femoral metaphysis (24) (Fig. S1B).…”

Section: Resultsmentioning

confidence: 99%

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Skeletal parasympathetic innervation communicates central IL-1 signals regulating bone mass accrual

Bajayo¹,

Bar²,

Dénes

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

144

162

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Bone mass accrual is a major determinant of skeletal mass, governed by bone remodeling, which consists of bone resorption by osteoclasts and bone formation by osteoblasts. Bone mass accrual is inhibited by sympathetic signaling centrally regulated through activation of receptors for serotonin, leptin, and ACh. However, skeletal activity of the parasympathetic nervous system (PSNS) has not been reported at the bone level. Here we report skeletal immune-positive fibers for the PSNS marker vesicular ACh transporter (VAChT). Pseudorabies virus inoculated into the distal femoral metaphysis is identifiable in the sacral intermediolateral cell column and central autonomic nucleus, demonstrating PSNS femoral innervation originating in the spinal cord. The PSNS neurotransmitter ACh targets nicotinic (nAChRs), but not muscarinic receptors in bone cells, affecting mainly osteoclasts. nAChR agonists up-regulate osteoclast apoptosis and restrain bone resorption. Mice deficient of the α 2 nAChR subunit have increased bone resorption and low bone mass. Silencing of the IL-1 receptor signaling in the central nervous system by brain-specific overexpression of the human IL-1 receptor antagonist (hIL1ra Ast +/+ mice) leads to very low skeletal VAChT expression and ACh levels. These mice also exhibit increased bone resorption and low bone mass. In WT but not in hIL1ra Ast +/+ mice, the cholinergic ACh esterase inhibitor pyridostigmine increases ACh levels and bone mass apparently by inhibiting bone resorption. Taken together, these results identify a previously unexplored key central IL-1-parasympathetic-bone axis that antagonizes the skeletal sympathetic tone, thus potently favoring bone mass accrual.autonomic nervous system | postnatal skeletal development

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Section: Resultsmentioning

confidence: 99%

“…Pseudorabies virus was injected into mouse or rat distal femoral metaphyses. Progression of immunoreactive pseudorabies virus was detected as described previously (24).…”

Section: Methodsmentioning

confidence: 99%

Skeletal parasympathetic innervation communicates central IL-1 signals regulating bone mass accrual

Bajayo¹,

Bar²,

Dénes

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

144

162

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“…Functional separation between the innervation of bone and bone morrow has yet to be established. Although application of neuroanatomical tract-tracing techniques to identifying the origin of the innervation of bone marrow versus the surrounding tissue is technically difficult, (Denes et al, 2005) recently reported the first neuroanatomical study to examine the origin for the neural innervation of bone marrow. Utilizing high concentrations of PRV, they demonstrated the transneuronal transport of the virus from femoral bone marrow to thoracolumbar paravertebral sympathetic ganglia and T8-L1 spinal sympathetic preganglion neurons.…”

Section: Innervation Of Bone Marrowmentioning

confidence: 99%

Autonomic innervation and regulation of the immune system (1987–2007)

Nance¹,

Sanders²

2007

Brain, Behavior, and Immunity

740

580

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Since 1987, only a few neuroanatomical studies have been conducted to identify the origin of innervation for the immune system. These studies demonstrated that all primary and secondary immune organs receive a substantial sympathetic innervation from sympathetic postganglionic neurons. Neither the thymus nor spleen receive any sensory neural innervation; however, there is evidence that lymph nodes and bone marrow may be innervated by sensory neurons located in dorsal root ganglia. There is no neuroanatomical evidence for a parasympathetic or vagal nerve supply to any immune organ. Thus, the primary pathway for the neural regulation of immune function is provided by the sympathetic nervous system (SNS) and its main neurotransmitter, norepinephrine (NE). Activation of the SNS primarily inhibits the activity of cells associated with the innate immune system, while it either enhances or inhibits the activity of cells associated with the acquired/adaptive immune system. Innate immune cells express both alpha and beta-adrenergic receptor subtypes, while T and B lymphocytes express adrenergic receptors of the beta2 subtype exclusively, except for murine Th2 cells that lack expression of any subtype. Via these adrenergic receptors, NE is able to regulate the level of immune cell activity by initiating a change in the level of cellular activity, which often involves a change in the level of gene expression for cytokines and antibodies.

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“…Preautonomic neural efferents in the brain stem control the bone marrow (Denes et al, 2005), and two-thirds of the projections originating from the ventrolateral medulla are considered ipsilateral (Moon et al, 2002). Hence, we investigated whether stroke could induce laterality in the brain or in the bone marrow.…”

Section: Lateralisation Of the Bone Marrow In Response To Experimentamentioning

confidence: 99%

“…Notably, the signals that trigger leukocyte mobilisation from the bone marrow in acute brain diseases are unknown and may represent potential targets for therapy. We showed previously that the bone marrow receives central autonomic innervation, which involves forebrain areas such as the insular and piriform cortex (Denes et al, 2005), which often become ischaemic after experimental stroke. It is also known that humoural factors, including cytokines and chemokines are rapidly elevated in both the brain and the periphery after stroke (Offner et al, 2006a).…”

Section: Introductionmentioning

confidence: 99%

Experimental Stroke-Induced Changes in the Bone Marrow Reveal Complex Regulation of Leukocyte Responses

Dénes

McColl

Leow-Dyke

et al. 2010

J Cereb Blood Flow Metab

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Stroke induces a systemic response that involves rapid activation of inflammatory cascades, followed later by immunodepression. Experimental stroke-induced responses in the bone marrow, which is the primary source of circulating monocytes and granulocytes, have not been investigated previously. We show that cerebral ischaemia induced early (4 hours) release of CXCR2-positive granulocytes from the bone marrow, which was associated with rapid systemic upregulation of CXCL1 (a ligand for CXCR2) and granulocyte-colony-stimulating factor, a key cytokine involved in the mobilisation of bone marrow leukocytes. This process involves rapid activation of nuclear factor-jB and p38 mitogen-activated protein kinase in bone marrow myeloid cells. T-cell numbers in the bone marrow increased after stroke, and bone marrow cells did not show suppressed cytokine response to bacterial endotoxin stimulation in vitro. Stroke-induced laterality observed in the brain stem and in the bone marrow indicates direct involvement of the autonomic nervous system in stroke-induced cell mobilisation. We also show that systemic inflammatory changes and leukocyte responses in the bone marrow are profoundly affected by both anaesthetic and surgical stress. We conclude that stroke influences leukocyte responses in the bone marrow through multiple mechanisms and suggest that preclinical studies should take into consideration the effect of surgical manipulation in experimental models of stroke.

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Central autonomic control of the bone marrow: Multisynaptic tract tracing by recombinant pseudorabies virus

Cited by 121 publications

References 76 publications

Skeletal parasympathetic innervation communicates central IL-1 signals regulating bone mass accrual

Skeletal parasympathetic innervation communicates central IL-1 signals regulating bone mass accrual

Autonomic innervation and regulation of the immune system (1987–2007)

Experimental Stroke-Induced Changes in the Bone Marrow Reveal Complex Regulation of Leukocyte Responses

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