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

Inoue, Tsuyoshi; Abe, Chikara; Sung, Sun-sang J.; Moscalu, Stefan; Jankowski, Jakub; Huang, Liping; Zhang, Pengcheng; Rosin, Diane L.; Guyenet, Patrice G.; Okusa, Mark D.

doi:10.1172/jci83658

Cited by 248 publications

(308 citation statements)

References 56 publications

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“…12). Interorgan trafficking of immune cells and dissemination of inflammatory cytokines are surely responsible for many of these effects, but the present study by Inoue, Abe et al again reinforces the view that neural mechanisms are also likely to contribute in important ways to this phenomenon (5). Indeed, in the course of their study, the authors replicated the previous observation (13) that renal sympathetic denervation profoundly decreases injury in one model of IRI.…”

Section: Discussionsupporting

confidence: 88%

“…Unfortunately, the ability of such an approach to treat AKI that has already started to progress is not a likely outcome, as the protective effect of neuroimmunomodulation only developed after a significant delay -VNS was effective at attenuating AKI when delivered at 24 hours but not at 2 hours prior to injury (5). Therefore, the most likely clinical use for this approach would be as a prophylactic measure in situations where the patient is at high risk of developing AKI.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

A wandering path toward prevention for acute kidney injury

Atkinson¹

2016

Journal of Clinical Investigation

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“…As mentioned earlier, animal models have shown that the spleen may play a key role in orchestrating signals from the vagus nerve to the immune system [84]. Adoptive transfer of a7nAChR-positive splenocytes from VNS-treated wild-type mice, but not from a7nAChR-knockout mice, protected against kidney ischaemia-reperfusion injury [85], indicating a role for the a7nAChR in this mechanism. Another study showed that VNS may result in reduced expression of IL-6 and TNF in the brain of rats after LPS injection into the trachea, specifically in the nucleus tractus solitarii where the afferent vagus nerve terminates, indicating that VNS could also change cytokine expression centrally [86].…”

Section: The Effects Of Vagus Nerve Stimulation On Inflammation In Humentioning

confidence: 83%

Balancing the autonomic nervous system to reduce inflammation in rheumatoid arthritis

et al. 2017

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Imbalance in the autonomic nervous system (ANS) has been observed in many established chronic autoimmune diseases, including rheumatoid arthritis (RA), which is a prototypic immune‐mediated inflammatory disease (IMID). We recently discovered that autonomic dysfunction precedes and predicts arthritis development in subjects at risk of developing seropositive RA. In addition, RA patients with relatively high vagus nerve tone (higher parasympathetic parameters, measured by heart rate variability) respond better to antirheumatic therapies. Together, these data suggest that the ANS may control inflammation in humans. This notion is supported by experimental studies in animal models of RA. We have found that stimulation of the so‐called cholinergic anti‐inflammatory pathway by efferent electrical vagus nerve stimulation (VNS) or pharmacological activation of the alpha7 subunit of nicotinic acetylcholine receptors (α7nAChR) improves clinical signs and symptoms of arthritis, reduces cytokine production and protects against progressive joint destruction. Conversely, increased arthritis activity was observed in alpha7nAChR knockout mice. These studies together with previous work in animal models of sepsis and other forms of inflammation provided the rationale for an experimental clinical trial in patients with RA. We could for the first time show that an implantable vagus nerve stimulator inhibits peripheral blood cytokine production in humans. VNS significantly inhibited TNF and IL‐6 production and improved RA disease severity, even in some patients with therapy‐resistant disease. This work strongly supports further studies using a bioelectronic approach to treat RA and other IMIDs.

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“…Burne-Taney et al [29] reported that nu/nu mice receiving spleen derived leukocytes from ischemic wild-type mice had significantly reduced renal injury compared with nu/nu mice receiving leukocytes from sham-operated, wild-type mice. Inoue et al [30] demonstrated that the renoprotective effects and the anti-inflammatory properties mediated by the stimulation of the vagus nerves depended on α7 nicotinic acetylcholine receptors-positive splenocytes. Andrés-Hernando et al [31] demonstrated that splenectomy exacerbated the proinflammatory response that occurred in ischemic AKI by removal of the anti-inflammatory cytokine IL-10.…”

Section: Discussionmentioning

confidence: 99%

Superagonistic CD28 Protects against Renal Ischemic Injury by Expansion of Regulatory T-Cell

Liang

Kuang

et al. 2017

Am J Nephrol

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Background: Regulatory T (Treg) cells are a highly suppressive subset of CD4⁺ lymphocytes and have recently been proved to be crucial to suppress the inflammatory responses of ischemic kidney injury. CD28 superagonists (CD28sa) are monoclonal antibodies that preferentially expand Treg cells without a T-cell receptor and a costimulatory signal. This study aims to test the protection and discover the mechanisms of CD28sa treatment against renal ischemia-reperfusion (IR) injury (IRI). Methods: Male C57BL/6N mice were treated with CD28sa via peritoneal injection (0.1 mg) 6 days before the induction of IRI, or with 18-min ischemic precondition (IPC). IRI was induced by bilateral clamping of renal pedicles for 35 min followed by reperfusion. The role of Treg expansion in renal protection conferred by CD28sa treatment was examined using anti-CD25 antibody. Results: CD28sa treatment alone significantly increased the percentage of Treg cells in the spleen (18.10 ± 2.00 vs. 6.64 ± 0.86%, p < 0.01), peripheral blood (16.43 ± 5.94 vs. 2.57 ± 1.09%, p < 0.01), and kidney (2.69 ± 0.90 vs. 0.53 ± 0.14%, p < 0.01) of C57BL/6N mice 6 days after the administration. Mice pretreated with CD28sa or IPC had less renal injury at 24 h after IRI with attenuation of renal tubular damage and lower serum creatinine compared with the mice that underwent renal IRI alone. The number of infiltrating macrophages in the kidney and IFN-γ secreting CD4⁺ T cells in peripheral blood were diminished in the CD28sa-IR group and the IPC-IR group. The renal protection bestowed by CD28sa or IPC was abolished by anti-CD25 antibody administration. Conclusions: Treg expansion induced by CD28sa ameliorated renal IRI.

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

Cited by 248 publications

References 56 publications

A wandering path toward prevention for acute kidney injury

A wandering path toward prevention for acute kidney injury

Balancing the autonomic nervous system to reduce inflammation in rheumatoid arthritis

Superagonistic CD28 Protects against Renal Ischemic Injury by Expansion of Regulatory T-Cell

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