Vagus nerve stimulation mediates protection from kidney ischemia-reperfusion injury through α7nAChR+ splenocytes
Tsuyoshi Inoue, … , Patrice G. Guyenet, Mark D. Okusa
Tsuyoshi Inoue, … , Patrice G. Guyenet, Mark D. Okusa
Published April 18, 2016
Citation Information: J Clin Invest. 2016;126(5):1939-1952. https://doi.org/10.1172/JCI83658.
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Research Article Nephrology

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

Abstract

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.

Authors

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

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Figure 10

Prior VNS does not change the number of macrophages infiltrating the kidney, but changes their phenotype.

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Prior VNS does not change the number of macrophages infiltrating the kid...
α7KO mice and WT (progeny controls) mice underwent IRI 24 hours after VNS or sham VNS treatment. Mice were euthanized after 0, 4, or 24 hours of reperfusion, and the number of macrophages/monocytes and granulocytes in the kidney was evaluated by flow cytometry (gating strategy in Supplemental Figure 2). (A and B) The number of macrophages/monocytes infiltrating the kidney increased with time after IRI in WT (A) and α7KO mice (B), but prior VNS did not change the number. (C and D) The number of granulocytes infiltrating the kidney increased with time after IRI in WT (C) and α7KO mice (D), and this increase was suppressed 24 hours after IRI in VNS-treated WT mice (C), but not in α7KO mice (D). (E and F) qPCR was performed using FACS-sorted macrophages/monocytes from the kidney of WT (E) and α7KO mice (F) (raw data in Supplemental Figure 3). Relative gene expressions compared with control group were calculated, and clustering was performed. Data were analyzed using 2-way ANOVA. Means were compared by post hoc multiple-comparison test (Tukey’s). *P < 0.05. n = 3 in A–D. n = 3 for control (untreated) and n = 6 for sham-IRI and VNS-IRI (E and F).