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Robin M. Mcallen - One of the best experts on this subject based on the ideXlab platform.
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anti Inflammatory Reflex action of splanchnic sympathetic nerves is distributed across abdominal organs
American Journal of Physiology-regulatory Integrative and Comparative Physiology, 2019Co-Authors: Davide Martelli, M J Mckinley, David G S Farmer, Robin M. McallenAbstract:The splanchnic anti-Inflammatory pathway has been proposed as the efferent arm of the Inflammatory Reflex. Although much evidence points to the spleen as the principal target organ where sympatheti...
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Reflex control of inflammation by sympathetic nerves not the vagus
The Journal of Physiology, 2014Co-Authors: Davide Martelli, Robin M. Mcallen, M J MckinleyAbstract:Key points It is believed that the CNS controls inflammation via the autonomic nervous system, but the strength of this action and the neural pathways responsible are unclear. In anaesthetized rats we measured the Inflammatory response to lipopolysaccharide (LPS, 60 μg kg−1, i.v.) by plasma tumour necrosis factor α (TNFα) levels 90 min later. Bilateral section of the splanchnic sympathetic nerves before LPS treatment resulted in a 5-fold increase in the plasma TNFα response, but bilateral vagotomy had no effect. LPS treatment strongly increased efferent activity in the splanchnic sympathetic nerve and its splenic branch; vagotomy did not affect this. These results show that, besides directly stimulating inflammation, LPS engages a powerful anti-Inflammatory Reflex that can inhibit the plasma TNFα response by 80%. The Reflex efferent arm is in the splanchnic sympathetic nerves; the vagi play no part. Abstract We investigated a neural Reflex that controls the strength of Inflammatory responses to immune challenge – the Inflammatory Reflex. In anaesthetized rats challenged with intravenous lipopolysaccharide (LPS, 60 μg kg−1), we found strong increases in plasma levels of the key Inflammatory mediator tumour necrosis factor α (TNFα) 90 min later. Those levels were unaffected by previous bilateral cervical vagotomy, but were enhanced approximately 5-fold if the greater splanchnic sympathetic nerves had been cut. Sham surgery had no effect, and plasma corticosterone levels were unaffected by nerve sections, so could not explain this result. Electrophysiological recordings demonstrated that efferent neural activity in the splanchnic nerve and its splenic branch was strongly increased by LPS treatment. Splenic nerve activity was dependent on inputs from the splanchnic nerves: vagotomy had no effect on the activity in either nerve. Together, these data demonstrate that immune challenge with this dose of LPS activates a neural Reflex that is powerful enough to cause an 80% suppression of the acute systemic Inflammatory response. The efferent arm of this Reflex is in the splanchnic sympathetic nerves, not the vagi as previously proposed. As with other physiological responses to immune challenge, the afferent pathway is presumptively humoral: the present data show that vagal afferents play no measurable part. Because inflammation sits at the gateway to immune responses, this Reflex could play an important role in immune function as well as Inflammatory diseases.
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Reflex control of inflammation by sympathetic nerves not the vagus
The Journal of Physiology, 2014Co-Authors: Davide Martelli, Robin M. Mcallen, M J MckinleyAbstract:We investigated a neural Reflex that controls the strength of Inflammatory responses to immune challenge - the Inflammatory Reflex. In anaesthetized rats challenged with intravenous lipopolysaccharide (LPS, 60 μg kg(-1)), we found strong increases in plasma levels of the key Inflammatory mediator tumour necrosis factor α (TNFα) 90 min later. Those levels were unaffected by previous bilateral cervical vagotomy, but were enhanced approximately 5-fold if the greater splanchnic sympathetic nerves had been cut. Sham surgery had no effect, and plasma corticosterone levels were unaffected by nerve sections, so could not explain this result. Electrophysiological recordings demonstrated that efferent neural activity in the splanchnic nerve and its splenic branch was strongly increased by LPS treatment. Splenic nerve activity was dependent on inputs from the splanchnic nerves: vagotomy had no effect on the activity in either nerve. Together, these data demonstrate that immune challenge with this dose of LPS activates a neural Reflex that is powerful enough to cause an 80% suppression of the acute systemic Inflammatory response. The efferent arm of this Reflex is in the splanchnic sympathetic nerves, not the vagi as previously proposed. As with other physiological responses to immune challenge, the afferent pathway is presumptively humoral: the present data show that vagal afferents play no measurable part. Because inflammation sits at the gateway to immune responses, this Reflex could play an important role in immune function as well as Inflammatory diseases.
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The cholinergic anti-Inflammatory pathway: A critical review
Autonomic Neuroscience, 2014Co-Authors: Davide Martelli, Michael J. Mckinley, Robin M. McallenAbstract:From a critical review of the evidence on the cholinergic anti-Inflammatory pathway and its mode of action, the following conclusions were reached. (1) Both local and systemic inflammation may be suppressed by electrical stimulation of the peripheral cut end of either vagus. (2) The spleen mediates most of the systemic Inflammatory response (measured by TNF-α production) to systemic endotoxin and is also the site where that response is suppressed by vagal stimulation. (3) The anti-Inflammatory effect of vagal stimulation depends on the presence of noradrenaline-containing nerve terminals in the spleen. (4) There is no disynaptic connection from the vagus to the spleen via the splenic sympathetic nerve: vagal stimulation does not drive action potentials in the splenic nerve. (5) Acetylcholine-synthesizing T lymphocytes provide an essential non-neural link in the anti-Inflammatory pathway from vagus to spleen. (6) Alpha-7 subunit-containing nicotinic receptors are essential for the vagal anti-Inflammatory action: their critical location is uncertain, but is suggested here to be on splenic sympathetic nerve terminals. (7) The vagal anti-Inflammatory pathway can be activated electrically or pharmacologically, but it is not the efferent arm of the Inflammatory Reflex response to endotoxemia.
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neural regulation of inflammation no neural connection from the vagus to splenic sympathetic neurons
Experimental Physiology, 2012Co-Authors: Bradford Bratton, Davide Martelli, M J Mckinley, David Trevaks, C R Anderson, Robin M. McallenAbstract:The 'Inflammatory Reflex' acts through efferent neural connections from the central nervous system to lymphoid organs, particularly the spleen, that suppress the production of Inflammatory cytokines. Stimulation of the efferent vagus has been shown to suppress inflammation in a manner dependent on the spleen and splenic nerves. The vagus does not innervate the spleen, so a synaptic connection from vagal preganglionic neurons to splenic sympathetic postganglionic neurons was suggested. We tested this idea in rats. In a preparatory operation, the anterograde tracer DiI was injected bilaterally into the dorsal motor nucleus of vagus and the retrograde tracer Fast Blue was injected into the spleen. On histological analysis 7-9 weeks later, 883 neurons were retrogradely labelled from the spleen with Fast Blue as follows: 89% in the suprarenal ganglia (65% left, 24% right); 11% in the left coeliac ganglion; but none in the right coeliac or either of the superior mesenteric ganglia. Vagal terminals anterogradely labelled with DiI were common in the coeliac but sparse in the suprarenal ganglia, and confocal analysis revealed no putative synaptic connection with any Fast Blue-labelled cell in either ganglion. Electrophysiological experiments in anaesthetized rats revealed no effect of vagal efferent stimulation on splenic nerve activity or on that of 15 single splenic-projecting neurons recorded in the suprarenal ganglion. Together, these findings indicate that vagal efferent neurons in the rat neither synapse with splenic sympathetic neurons nor drive their ongoing activity.
Davide Martelli - One of the best experts on this subject based on the ideXlab platform.
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sympathetic nerves control bacterial clearance
Scientific Reports, 2020Co-Authors: Yugeesh R Lankadeva, Clive N May, M J Mckinley, Melanie R Neeland, Dianna M Hocking, Roy M Robinsbrowne, Sammy Bedoui, David G S Farmer, S R Bailey, Davide MartelliAbstract:A neural Reflex mediated by the splanchnic sympathetic nerves regulates systemic inflammation in negative feedback fashion, but its consequences for host responses to live infection are unknown. To test this, conscious instrumented sheep were infected intravenously with live E. coli bacteria and followed for 48 h. A month previously, animals had undergone either bilateral splanchnic nerve section or a sham operation. As established for rodents, sheep with cut splanchnic nerves mounted a stronger systemic Inflammatory response: higher blood levels of tumor necrosis factor alpha and interleukin-6 but lower levels of the anti-Inflammatory cytokine interleukin-10, compared with sham-operated animals. Sequential blood cultures revealed that most sham-operated sheep maintained high circulating levels of live E. coli throughout the 48-h study period, while all sheep without splanchnic nerves rapidly cleared their bacteraemia and recovered clinically. The sympathetic Inflammatory Reflex evidently has a profound influence on the clearance of systemic bacterial infection.
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anti Inflammatory Reflex action of splanchnic sympathetic nerves is distributed across abdominal organs
American Journal of Physiology-regulatory Integrative and Comparative Physiology, 2019Co-Authors: Davide Martelli, M J Mckinley, David G S Farmer, Robin M. McallenAbstract:The splanchnic anti-Inflammatory pathway has been proposed as the efferent arm of the Inflammatory Reflex. Although much evidence points to the spleen as the principal target organ where sympatheti...
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the splanchnic anti Inflammatory pathway could it be the efferent arm of the Inflammatory Reflex
Experimental Physiology, 2016Co-Authors: Davide Martelli, David G S Farmer, Song T YaoAbstract:What is the topic of this review? We review the current literature on the neural Reflex termed the 'Inflammatory Reflex' that inhibits an excessive release of Inflammatory mediators in response to an immune challenge. What advances does it highlight? The original model proposed that the Inflammatory Reflex is a vago-vagal Reflex that controls immune function. We posit that, in the endotoxaemic animal model, the vagus nerves do not appear to play a role. The evidence suggests that the efferent motor pathway, termed here the 'splanchnic anti-Inflammatory pathway', is purely sympathetic, travelling via the greater splanchnic nerves to regulate the ensuing Inflammatory response to immune challenges. Exposure to immune challenges results in the development of inflammation. An insufficient Inflammatory response can be life-threatening, whereas an exaggerated response is also detrimental because it causes tissue damage and, in extreme cases, septic shock that can lead to death. Hence, inflammation must be finely regulated. It is generally accepted that the brain inhibits inflammation induced by an immune challenge in two main ways: humorally, by activating the hypothalamic-pituitary-adrenal axis to release glucocorticoids; and neurally, via a mechanism that has been termed the 'Inflammatory Reflex'. The efferent arm of this Reflex (the neural-to-immune link) was thought to be the 'cholinergic anti-Inflammatory pathway'. Here, we discuss data that support the hypothesis that the vagus nerves play no role in the control of inflammation in the endotoxaemic animal model. We have shown and posit that it is the greater splanchnic nerves that are activated in response to the immune challenge and that, in turn, drive postganglionic sympathetic neurons to inhibit inflammation.
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Reflex control of inflammation by sympathetic nerves not the vagus
The Journal of Physiology, 2014Co-Authors: Davide Martelli, Robin M. Mcallen, M J MckinleyAbstract:Key points It is believed that the CNS controls inflammation via the autonomic nervous system, but the strength of this action and the neural pathways responsible are unclear. In anaesthetized rats we measured the Inflammatory response to lipopolysaccharide (LPS, 60 μg kg−1, i.v.) by plasma tumour necrosis factor α (TNFα) levels 90 min later. Bilateral section of the splanchnic sympathetic nerves before LPS treatment resulted in a 5-fold increase in the plasma TNFα response, but bilateral vagotomy had no effect. LPS treatment strongly increased efferent activity in the splanchnic sympathetic nerve and its splenic branch; vagotomy did not affect this. These results show that, besides directly stimulating inflammation, LPS engages a powerful anti-Inflammatory Reflex that can inhibit the plasma TNFα response by 80%. The Reflex efferent arm is in the splanchnic sympathetic nerves; the vagi play no part. Abstract We investigated a neural Reflex that controls the strength of Inflammatory responses to immune challenge – the Inflammatory Reflex. In anaesthetized rats challenged with intravenous lipopolysaccharide (LPS, 60 μg kg−1), we found strong increases in plasma levels of the key Inflammatory mediator tumour necrosis factor α (TNFα) 90 min later. Those levels were unaffected by previous bilateral cervical vagotomy, but were enhanced approximately 5-fold if the greater splanchnic sympathetic nerves had been cut. Sham surgery had no effect, and plasma corticosterone levels were unaffected by nerve sections, so could not explain this result. Electrophysiological recordings demonstrated that efferent neural activity in the splanchnic nerve and its splenic branch was strongly increased by LPS treatment. Splenic nerve activity was dependent on inputs from the splanchnic nerves: vagotomy had no effect on the activity in either nerve. Together, these data demonstrate that immune challenge with this dose of LPS activates a neural Reflex that is powerful enough to cause an 80% suppression of the acute systemic Inflammatory response. The efferent arm of this Reflex is in the splanchnic sympathetic nerves, not the vagi as previously proposed. As with other physiological responses to immune challenge, the afferent pathway is presumptively humoral: the present data show that vagal afferents play no measurable part. Because inflammation sits at the gateway to immune responses, this Reflex could play an important role in immune function as well as Inflammatory diseases.
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Reflex control of inflammation by sympathetic nerves not the vagus
The Journal of Physiology, 2014Co-Authors: Davide Martelli, Robin M. Mcallen, M J MckinleyAbstract:We investigated a neural Reflex that controls the strength of Inflammatory responses to immune challenge - the Inflammatory Reflex. In anaesthetized rats challenged with intravenous lipopolysaccharide (LPS, 60 μg kg(-1)), we found strong increases in plasma levels of the key Inflammatory mediator tumour necrosis factor α (TNFα) 90 min later. Those levels were unaffected by previous bilateral cervical vagotomy, but were enhanced approximately 5-fold if the greater splanchnic sympathetic nerves had been cut. Sham surgery had no effect, and plasma corticosterone levels were unaffected by nerve sections, so could not explain this result. Electrophysiological recordings demonstrated that efferent neural activity in the splanchnic nerve and its splenic branch was strongly increased by LPS treatment. Splenic nerve activity was dependent on inputs from the splanchnic nerves: vagotomy had no effect on the activity in either nerve. Together, these data demonstrate that immune challenge with this dose of LPS activates a neural Reflex that is powerful enough to cause an 80% suppression of the acute systemic Inflammatory response. The efferent arm of this Reflex is in the splanchnic sympathetic nerves, not the vagi as previously proposed. As with other physiological responses to immune challenge, the afferent pathway is presumptively humoral: the present data show that vagal afferents play no measurable part. Because inflammation sits at the gateway to immune responses, this Reflex could play an important role in immune function as well as Inflammatory diseases.
Kevin J Tracey - One of the best experts on this subject based on the ideXlab platform.
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Investigational treatment of rheumatoid arthritis with a vibrotactile device applied to the external ear
BMC, 2019Co-Authors: Meghan E Addorisio, Valentin A Pavlov, Gavin H Imperato, Alex F De Vos, Steve Forti, Richard S Goldstein, Tom Van Der Poll, Huan Yang, Betty Diamond, Kevin J TraceyAbstract:Abstract Background Rheumatoid arthritis (RA) is a chronic and debilitating Inflammatory disease characterized by extensive joint tissue inflammation. Implantable bioelectronic devices targeting the Inflammatory Reflex reduce TNF production and inflammation in preclinical models of Inflammatory disease, and in patients with RA and Crohn’s disease. Here, we assessed the effect of applying a vibrotactile device to the cymba concha of the external ear on Inflammatory responses in healthy subjects, as well as its effect on disease activity in RA patients. Methods Six healthy subjects received vibrotactile treatment at the cymba concha, and TNF production was analyzed at different time points post-stimulation. In a separate study, nineteen healthy subjects were enrolled in a randomized cross-over study, and effects of vibrotactile treatment at either the cymba concha or gastrocnemius on cytokine levels were assessed. In addition, the clinical efficacy of vibrotactile treatment on disease activity in RA was assessed in nine patients with RA in a prospective interventional study. Results Vibrotactile treatment at the cymba concha reduced TNF levels, and the suppressive effect persisted up to 24 h. In the cross-over study with 19 healthy subjects, vibrotactile treatment at the cymba concha but not at the gastrocnemius significantly reduced TNF, IL-1β, and IL-6 levels compared to pre-treatment baseline (TNF p
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optogenetic stimulation of brain cholinergic networks suppresses inflammation
Journal of Immunology, 2016Co-Authors: Valentin A Pavlov, Sangeeta S Chavan, Kevin J Tracey, Kurt R Lehner, Harold A Silverman, Tea TsaavaAbstract:Brain cholinergic muscarinic acetylcholine receptor (mAChR) signaling regulates peripheral inflammation via the Inflammatory Reflex ( Nat Rev Endocrinol, 2012, 8:743). Here we provide further insight into this regulation by utilizing optogenetic stimulation, a method allowing precise spatiotemporal neuronal activation. Laser light (473 nm) and transgenic mice expressing light activated channelrhodopsin-2 coupled to a fluorescent protein (ChR2-YFP) under the control of the choline acetyl transferase (ChAT) promoter were used. Optogenetic stimulation of the medial septum, a major source of brain cholinergic output to areas with abundant M1 mAChR localization significantly suppressed serum TNF levels, as compared to sham stimulation (P 0.0398) in ChAT-ChR2-YFP mice during endotoxemia. In contrast to ChAT-ChR2-YFP mice, using the same approach in control (non-carrier) endotoxemic mice did not alter serum TNF. In addition, intracerebroventricular administration of the selective M1 mAChR agonist benzyl quinolone carboxylic acid (5 μg/kg) significantly decreased serum TNF, as compared to vehicle administration (P 0.0180) in C57Bl/6 mice during endotoxemia. These results from ongoing studies reveal a role for forebrain cholinergic M1 mAChR-mediated signaling in controlling peripheral inflammation. These findings may be of interest for development of new approaches for selective brain modulation for the treatment of Inflammatory conditions.
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the vagus nerve and the Inflammatory Reflex linking immunity and metabolism
Nature Reviews Endocrinology, 2012Co-Authors: Valentin A Pavlov, Kevin J TraceyAbstract:The vagus nerve has an important role in regulation of metabolic homeostasis, and efferent vagus nerve-mediated cholinergic signalling controls immune function and proInflammatory responses via the Inflammatory Reflex. Dysregulation of metabolism and immune function in obesity are associated with chronic inflammation, a critical step in the pathogenesis of insulin resistance and type 2 diabetes mellitus. Cholinergic mechanisms within the Inflammatory Reflex have, in the past 2 years, been implicated in attenuating obesity-related inflammation and metabolic complications. This knowledge has led to the exploration of novel therapeutic approaches in the treatment of obesity-related disorders.
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rethinking inflammation neural circuits in the regulation of immunity
Immunological Reviews, 2012Co-Authors: Peder S Olofsson, Mauricio Rosasballina, Yaakov A Levine, Kevin J TraceyAbstract:Neural Reflex circuits regulate cytokine release to prevent potentially damaging inflammation and maintain homeostasis. In the Inflammatory Reflex, sensory input elicited by infection or injury travels through the afferent vagus nerve to integrative regions in the brainstem, and efferent nerves carry outbound signals that terminate in the spleen and other tissues. Neurotransmitters from peripheral autonomic nerves subsequently promote acetylcholine-release from a subset of CD4(+) T cells that relay the neural signal to other immune cells, e.g. through activation of α7 nicotinic acetylcholine receptors on macrophages. Here, we review recent progress in the understanding of the Inflammatory Reflex and discuss potential therapeutic implications of current findings in this evolving field.
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Reflex principles of immunological homeostasis
Annual Review of Immunology, 2012Co-Authors: Ulf Andersson, Kevin J TraceyAbstract:The reasoning that neural Reflexes maintain homeostasis in other body organs, and that the immune system is innervated, prompted a search for neural circuits that regulate innate and adaptive immunity. This elucidated the Inflammatory Reflex, a prototypical Reflex circuit that maintains immunological homeostasis. Molecular products of infection or injury activate sensory neurons traveling to the brainstem in the vagus nerve. The arrival of these incoming signals generates action potentials that travel from the brainstem to the spleen and other organs. This culminates in T cell release of acetylcholine, which interacts with α7 nicotinic acetylcholine receptors (α7 nAChR) on immunocompetent cells to inhibit cytokine release in macrophages. Herein is reviewed the neurophysiological basis of Reflexes that provide stability to the immune system, the neural- and receptor-dependent mechanisms, and the potential opportunities for developing novel therapeutic devices and drugs that target neural pathways to treat Inflammatory diseases.
M J Mckinley - One of the best experts on this subject based on the ideXlab platform.
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sympathetic nerves control bacterial clearance
Scientific Reports, 2020Co-Authors: Yugeesh R Lankadeva, Clive N May, M J Mckinley, Melanie R Neeland, Dianna M Hocking, Roy M Robinsbrowne, Sammy Bedoui, David G S Farmer, S R Bailey, Davide MartelliAbstract:A neural Reflex mediated by the splanchnic sympathetic nerves regulates systemic inflammation in negative feedback fashion, but its consequences for host responses to live infection are unknown. To test this, conscious instrumented sheep were infected intravenously with live E. coli bacteria and followed for 48 h. A month previously, animals had undergone either bilateral splanchnic nerve section or a sham operation. As established for rodents, sheep with cut splanchnic nerves mounted a stronger systemic Inflammatory response: higher blood levels of tumor necrosis factor alpha and interleukin-6 but lower levels of the anti-Inflammatory cytokine interleukin-10, compared with sham-operated animals. Sequential blood cultures revealed that most sham-operated sheep maintained high circulating levels of live E. coli throughout the 48-h study period, while all sheep without splanchnic nerves rapidly cleared their bacteraemia and recovered clinically. The sympathetic Inflammatory Reflex evidently has a profound influence on the clearance of systemic bacterial infection.
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anti Inflammatory Reflex action of splanchnic sympathetic nerves is distributed across abdominal organs
American Journal of Physiology-regulatory Integrative and Comparative Physiology, 2019Co-Authors: Davide Martelli, M J Mckinley, David G S Farmer, Robin M. McallenAbstract:The splanchnic anti-Inflammatory pathway has been proposed as the efferent arm of the Inflammatory Reflex. Although much evidence points to the spleen as the principal target organ where sympatheti...
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Reflex control of inflammation by sympathetic nerves not the vagus
The Journal of Physiology, 2014Co-Authors: Davide Martelli, Robin M. Mcallen, M J MckinleyAbstract:Key points It is believed that the CNS controls inflammation via the autonomic nervous system, but the strength of this action and the neural pathways responsible are unclear. In anaesthetized rats we measured the Inflammatory response to lipopolysaccharide (LPS, 60 μg kg−1, i.v.) by plasma tumour necrosis factor α (TNFα) levels 90 min later. Bilateral section of the splanchnic sympathetic nerves before LPS treatment resulted in a 5-fold increase in the plasma TNFα response, but bilateral vagotomy had no effect. LPS treatment strongly increased efferent activity in the splanchnic sympathetic nerve and its splenic branch; vagotomy did not affect this. These results show that, besides directly stimulating inflammation, LPS engages a powerful anti-Inflammatory Reflex that can inhibit the plasma TNFα response by 80%. The Reflex efferent arm is in the splanchnic sympathetic nerves; the vagi play no part. Abstract We investigated a neural Reflex that controls the strength of Inflammatory responses to immune challenge – the Inflammatory Reflex. In anaesthetized rats challenged with intravenous lipopolysaccharide (LPS, 60 μg kg−1), we found strong increases in plasma levels of the key Inflammatory mediator tumour necrosis factor α (TNFα) 90 min later. Those levels were unaffected by previous bilateral cervical vagotomy, but were enhanced approximately 5-fold if the greater splanchnic sympathetic nerves had been cut. Sham surgery had no effect, and plasma corticosterone levels were unaffected by nerve sections, so could not explain this result. Electrophysiological recordings demonstrated that efferent neural activity in the splanchnic nerve and its splenic branch was strongly increased by LPS treatment. Splenic nerve activity was dependent on inputs from the splanchnic nerves: vagotomy had no effect on the activity in either nerve. Together, these data demonstrate that immune challenge with this dose of LPS activates a neural Reflex that is powerful enough to cause an 80% suppression of the acute systemic Inflammatory response. The efferent arm of this Reflex is in the splanchnic sympathetic nerves, not the vagi as previously proposed. As with other physiological responses to immune challenge, the afferent pathway is presumptively humoral: the present data show that vagal afferents play no measurable part. Because inflammation sits at the gateway to immune responses, this Reflex could play an important role in immune function as well as Inflammatory diseases.
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Reflex control of inflammation by sympathetic nerves not the vagus
The Journal of Physiology, 2014Co-Authors: Davide Martelli, Robin M. Mcallen, M J MckinleyAbstract:We investigated a neural Reflex that controls the strength of Inflammatory responses to immune challenge - the Inflammatory Reflex. In anaesthetized rats challenged with intravenous lipopolysaccharide (LPS, 60 μg kg(-1)), we found strong increases in plasma levels of the key Inflammatory mediator tumour necrosis factor α (TNFα) 90 min later. Those levels were unaffected by previous bilateral cervical vagotomy, but were enhanced approximately 5-fold if the greater splanchnic sympathetic nerves had been cut. Sham surgery had no effect, and plasma corticosterone levels were unaffected by nerve sections, so could not explain this result. Electrophysiological recordings demonstrated that efferent neural activity in the splanchnic nerve and its splenic branch was strongly increased by LPS treatment. Splenic nerve activity was dependent on inputs from the splanchnic nerves: vagotomy had no effect on the activity in either nerve. Together, these data demonstrate that immune challenge with this dose of LPS activates a neural Reflex that is powerful enough to cause an 80% suppression of the acute systemic Inflammatory response. The efferent arm of this Reflex is in the splanchnic sympathetic nerves, not the vagi as previously proposed. As with other physiological responses to immune challenge, the afferent pathway is presumptively humoral: the present data show that vagal afferents play no measurable part. Because inflammation sits at the gateway to immune responses, this Reflex could play an important role in immune function as well as Inflammatory diseases.
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neural regulation of inflammation no neural connection from the vagus to splenic sympathetic neurons
Experimental Physiology, 2012Co-Authors: Bradford Bratton, Davide Martelli, M J Mckinley, David Trevaks, C R Anderson, Robin M. McallenAbstract:The 'Inflammatory Reflex' acts through efferent neural connections from the central nervous system to lymphoid organs, particularly the spleen, that suppress the production of Inflammatory cytokines. Stimulation of the efferent vagus has been shown to suppress inflammation in a manner dependent on the spleen and splenic nerves. The vagus does not innervate the spleen, so a synaptic connection from vagal preganglionic neurons to splenic sympathetic postganglionic neurons was suggested. We tested this idea in rats. In a preparatory operation, the anterograde tracer DiI was injected bilaterally into the dorsal motor nucleus of vagus and the retrograde tracer Fast Blue was injected into the spleen. On histological analysis 7-9 weeks later, 883 neurons were retrogradely labelled from the spleen with Fast Blue as follows: 89% in the suprarenal ganglia (65% left, 24% right); 11% in the left coeliac ganglion; but none in the right coeliac or either of the superior mesenteric ganglia. Vagal terminals anterogradely labelled with DiI were common in the coeliac but sparse in the suprarenal ganglia, and confocal analysis revealed no putative synaptic connection with any Fast Blue-labelled cell in either ganglion. Electrophysiological experiments in anaesthetized rats revealed no effect of vagal efferent stimulation on splenic nerve activity or on that of 15 single splenic-projecting neurons recorded in the suprarenal ganglion. Together, these findings indicate that vagal efferent neurons in the rat neither synapse with splenic sympathetic neurons nor drive their ongoing activity.
Patrice G. Guyenet - One of the best experts on this subject based on the ideXlab platform.
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C1 neurons mediate a stress-induced anti-Inflammatory Reflex in mice
Nature neuroscience, 2017Co-Authors: Chikara Abe, Tsuyoshi Inoue, Mabel A Inglis, Kenneth E. Viar, Liping Huang, Diane L. Rosin, Ruth L. Stornetta, Mark D. Okusa, Patrice G. GuyenetAbstract:C1 neurons, located in the medulla oblongata, mediate adaptive autonomic responses to physical stressors (for example, hypotension, hemorrhage and presence of lipopolysaccharides). We describe here a powerful anti-Inflammatory effect of restraint stress, mediated by C1 neurons: protection against renal ischemia-reperfusion injury. Restraint stress or optogenetic C1 neuron (C1) stimulation (10 min) protected mice from ischemia-reperfusion injury (IRI). The protection was reproduced by injecting splenic T cells that had been preincubated with noradrenaline or splenocytes harvested from stressed mice. Stress-induced IRI protection was absent in Chrna7 knockout (a7nAChR-/-) mice and greatly reduced by destroying or transiently inhibiting C1. The protection conferred by C1 stimulation was eliminated by splenectomy, ganglionic-blocker administration or β2-adrenergic receptor blockade. Although C1 stimulation elevated plasma corticosterone and increased both vagal and sympathetic nerve activity, C1-mediated IRI protection persisted after subdiaphragmatic vagotomy or corticosterone receptor blockade. Overall, acute stress attenuated IRI by activating a cholinergic, predominantly sympathetic, anti-Inflammatory pathway. C1s were necessary and sufficient to mediate this effect.
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vagus nerve stimulation mediates protection from kidney ischemia reperfusion injury through α7nachr splenocytes
Journal of Clinical Investigation, 2016Co-Authors: Tsuyoshi Inoue, Liping Huang, Diane L. Rosin, Patrice G. Guyenet, Sunsang J Sung, Stefan Moscalu, Jakub Jankowski, Hong Ye, Mark D. OkusaAbstract:The nervous and immune systems interact in complex ways to maintain homeostasis and respond to stress or injury, and rapid nerve conduction can provide instantaneous input for modulating inflammation. The Inflammatory Reflex referred to as the cholinergic antiInflammatory pathway regulates innate and adaptive immunity, and modulation of this Reflex by vagus nerve stimulation (VNS) is effective in various Inflammatory disease models, such as rheumatoid arthritis and Inflammatory bowel disease. Effectiveness of VNS in these models necessitates the integration of neural signals and α7 nicotinic acetylcholine receptors (α7nAChRs) on splenic macrophages. Here, we sought to determine whether electrical stimulation of the vagus nerve attenuates kidney ischemia-reperfusion injury (IRI), which promotes the release of proInflammatory molecules. Stimulation of vagal afferents or efferents in mice 24 hours before IRI markedly attenuated acute kidney injury (AKI) and decreased plasma TNF. Furthermore, this protection was abolished in animals in which splenectomy was performed 7 days before VNS and IRI. In mice lacking α7nAChR, prior VNS did not prevent IRI. Conversely, adoptive transfer of VNS-conditioned α7nAChR splenocytes conferred protection to recipient mice subjected to IRI. Together, these results demonstrate that VNS-mediated attenuation of AKI and systemic inflammation depends on α7nAChR-positive splenocytes.
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electrical stimulation of the cervical vagus nerve protects against renal ischemia reperfusion injury
The FASEB Journal, 2015Co-Authors: Chikara Abe, Tsuyoshi Inoue, Mark D. Okusa, Patrice G. GuyenetAbstract:The Inflammatory Reflex acts via connections between the CNS and lymphoid organs, inc the spleen, to suppress the production of Inflammatory cytokines. Such Reflex can be elicited by electrically s...