Reflex control of inflammation by sympathetic nerves, not the vagus

Martelli, Davide; Yao, Song T.; McKinley, Michael J.; McAllen, Robin M.

doi:10.1113/jphysiol.2013.268573

Cited by 199 publications

(272 citation statements)

References 43 publications

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“…More specifically, vagal preganglionic neurons were thought to contact and activate noradrenergic postganglionic neurons coursing in the splenic nerve. However, no anatomical or electrophysiological evidence of such synapses has been found (38), and we have confirmed that VNS does not elicit a detectable evoked response in the splenic nerve of anesthetized rats (C. Abe, unpublished observations). Interestingly, the spleen seems to be an exception among +/-(α7HE), and α7KO mice underwent VNS 24 hours prior to IRI.…”

Section: Neural Pathways Responsible For the Protective Effect Of Vnssupporting

confidence: 51%

“…Clearly, under anesthesia, vagal afferent stimulation evokes a response in sympathetic nerves and this response does have an excitatory component (29). In addition, the sympathetic system facilitates the rapid inflammatory response (increased TNF-α) elicited by an acute injection of LPS in anesthetized rats (38). However, the vagosympathetic reflex hypothesis does not explain satisfactorily why the antiinflammatory effect is elicited by stimulating the peripheral end of the cut vagus nerve (24), an observation replicated in the present renal ischemia model; this hypothesis also does not explain why the protective effect of VNS is delayed (VNS done 10 minutes before ischemia offers no protection) and long lasting (at least 2 days).…”

Section: 6mentioning

confidence: 99%

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Vagus nerve stimulation mediates protection from kidney ischemia-reperfusion injury through α7nAChR+ splenocytes

Inoue¹,

Abe²,

Sung³

et al. 2016

Journal of Clinical Investigation

242

296

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) for measuring NE, the George F. O'Brien Center, University of Alabama (P30DK079337; principal investigator, Anupam Agarwal) for measuring plasma creatinine by LC-MS, the UVA Research Histology Core for their assistance in preparation of histology slides, and the UVA Flow Cytometry Facility for sample analysis using the Luminex 100 IS system and FACS sorting using BD Influx. We also thank Primetech Corp. (Tokyo, Japan) for supplying the iPRECIO microinfusion pump system.

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Section: Neural Pathways Responsible For the Protective Effect Of Vnssupporting

confidence: 51%

Section: 6mentioning

confidence: 99%

Vagus nerve stimulation mediates protection from kidney ischemia-reperfusion injury through α7nAChR+ splenocytes

Inoue¹,

Abe²,

Sung³

et al. 2016

Journal of Clinical Investigation

242

296

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“…24 Nevertheless, vagus nerve stimulation by centrally acting muscarinic agonists, such as CNI-1493, has been shown to suppress peripheral inflammatory responses that can be prevented by vagotomy, demonstrating that the vagus is an essential efferent pathway of the central cholinergic antiinflammatory pathway. 25 Assessment of HRV has been recognized to provide reliable, noninvasive information on the activity of the autonomic nervous system, including its vagal and sympathetic components.…”

Section: Strokementioning

confidence: 99%

Cholinergic Pathway Suppresses Pulmonary Innate Immunity Facilitating Pneumonia After Stroke

Engel¹,

Akyüz

Gonçalves

et al. 2015

Stroke

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T he management of medical complications is one of the most critical factors in the therapy of stroke because 95% of stroke patients experience at least one relevant medical complication in the first 3 months after stroke. 1 In both experimental and clinical studies, infections are the most common complication after stroke.2 Among these, pneumonia is the most relevant poststroke infection, 3 accounting for the highest attributable mortality after stroke. 4 To maintain body homeostasis in response to challenges from the environment, the nervous and immune systems are closely interconnected in an intense bidirectional communication. 5 Recent experimental and clinical evidence indicates that central nervous system injuries like stroke, spinal cord injury, or traumatic brain injury disturb the normally well-balanced interplay between these 2 supersystems, resulting in a profound and long-lasting immunodepression. 6,7 Overactivation of the sympathetic nervous system after stroke was shown to mediate suppression of peripheral cellular immune responses and to contribute to development of poststroke bacterial lung infections. [8][9][10] However, changes in the pulmonary immune compartment and the underlying mechanisms of impaired antibacterial lung immune responses after stroke are currently not understood.Besides resident lung immune cells, such as alveolar macrophages (MΦ), alveolar epithelial cells (AEC) express Background and Purpose-Temporary immunosuppression has been identified as a major risk factor for the development of pneumonia after acute central nervous system injury. Although overactivation of the sympathetic nervous system was previously shown to mediate suppression of systemic cellular immune responses after stroke, the role of the parasympathetic cholinergic anti-inflammatory pathway in the antibacterial defense in lung remains largely elusive. Methods-The middle cerebral artery occlusion model in mice was used to examine the influence of the parasympathetic nervous system on poststroke immunosuppression. We used heart rate variability measurement by telemetry, vagotomy, α7 nicotinic acetylcholine receptor-deficient mice, and parasympathomimetics (nicotine, PNU282987) to measure and modulate parasympathetic activity. Results-Here, we demonstrate a rapidly increased parasympathetic activity in mice after experimental stroke. Inhibition of cholinergic signaling by either vagotomy or by using α7 nicotinic acetylcholine receptor-deficient mice reversed pulmonary immune hyporesponsiveness and prevented pneumonia after stroke. In vivo and ex vivo studies on the role of α7 nicotinic acetylcholine receptor on different lung cells using bone marrow chimeric mice and isolated primary cells indicated that not only macrophages but also alveolar epithelial cells are a major cellular target of cholinergic antiinflammatory signaling in the lung. 12 Both MΦ and lung epithelial cells have been shown to express the α7 nicotinergic acetylcholine receptor (α7nAChR), 13 which has been identified as a crucial downstre...

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“…in the splenic nerve, as initially thought (11). Moreover, vagal stimulation does not produce an evoked response in the splenic nerve, indicating that a vagal-vagal reflex is unlikely to be a central mechanism of CAP activation.…”

Section: Discussionmentioning

confidence: 55%

A wandering path toward prevention for acute kidney injury

Atkinson¹

2016

Journal of Clinical Investigation

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A wandering path toward prevention for acute kidney injury Simon J. AtkinsonDepartment of Biology, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana, USA. Acute kidney injury: challenges for therapy developmentAcute kidney injury (AKI) remains a serious complication in hospitalized patients, especially those that are critically ill (1, 2), and results in significant mortality and morbidity in this population. Those individuals that develop AKI and survive are at extremely high risk of progressing to chronic kidney disease. AKI is almost invariably diagnosed in conjunction with a set of comorbid conditions, such as multiorgan sepsis or congestive heart failure, or in the aftermath of major cardiothoracic surgery. Basic research on AKI is complicated by the challenge of isolating and dissecting the mechanisms of AKI in animal or in vitro models while retaining relevance to the typically complicated clinical presentation seen in patients in the ICU. This fundamental challenge has limited progress in the identification of novel preventative measures or treatments for AKI that might improve upon the largely supportive measures that are currently employed (3). Researchers, physicians, and patients could sorely use some serendipitous findings that, like those of the three princes of Serendip (4), might advance their quest and put an end to their wanderings in search of an answer. In this issue, Inoue, Abe, and colleagues (5) build on just such a finding and suggest a new path forward. Specifically, these authors have uncovered neuroimmunomodulatory mechanisms that are amenable to therapeutic intervention and have potential to contribute additional strategies for limiting AKI. This line of research by Mark Okusa and colleagues began (6) with the hypothesis that preconditioning the renal vasculature with contrast-enhanced ultrasound would stimulate increased blood flow to the kidney and thereby attenuate ischemia-reperfusion injury (IRI) and consequent AKI. Surprisingly, the amelioration of IRI by prior ultrasound exposure did not require the introduction of contrast, nor did it require that the kidney itself be targeted with the ultrasound probe. Instead, exposure of the spleen was determined to be key to the protective effect, and a correlation between spleen enlargement and the ability to recruit CD4 + T cells to the spleen was found. Together, these results suggested that ultrasound stimulation might invoke an antiinflammatory response, leading Okusa and colleagues to propose that this protective effect was due to the known ability of certain ultrasound frequencies to stimulate nerves. The proposed mechanism of action ( Figure 1) involves ultrasound activation of adrenergic neurons innervating the spleen, stimulation of CD4 + cells via β-adrenergic receptors, consequent release of acetylcholine by T cells, and then stimulation of nicotinic cholinergic receptors on myeloid/macrophage cells. Pharmacologic studies have implicated stimulation of α7 nicotinic acetylcholine receptors (α7nAChRs) prese...

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Reflex control of inflammation by sympathetic nerves, not the vagus

Cited by 199 publications

References 43 publications

Vagus nerve stimulation mediates protection from kidney ischemia-reperfusion injury through α7nAChR+ splenocytes

Vagus nerve stimulation mediates protection from kidney ischemia-reperfusion injury through α7nAChR+ splenocytes

Cholinergic Pathway Suppresses Pulmonary Innate Immunity Facilitating Pneumonia After Stroke

A wandering path toward prevention for acute kidney injury

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