Constitutive Vagus Nerve Activation Modulates Immune Suppression in Sepsis Survivors
Patients surviving a septic episode exhibit persistent immune impairment and increased mortality due to enhanced vulnerability to infections. In the present study, using the cecal ligation and puncture (CLP) model of polymicrobial sepsis, we addressed the hypothesis that altered vagus nerve activity...
Main Authors: | , , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Frontiers Media S.A.
2018-09-01
|
Series: | Frontiers in Immunology |
Subjects: | |
Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2018.02032/full |
id |
doaj-4a0ebd6aa74c41bb97bd020ab28a5ab7 |
---|---|
record_format |
Article |
spelling |
doaj-4a0ebd6aa74c41bb97bd020ab28a5ab72020-11-24T22:30:23ZengFrontiers Media S.A.Frontiers in Immunology1664-32242018-09-01910.3389/fimmu.2018.02032405946Constitutive Vagus Nerve Activation Modulates Immune Suppression in Sepsis SurvivorsMinakshi Rana0Yurong Fei-Bloom1Myoungsun Son2Andrea La Bella3Mahendar Ochani4Yaakov A. Levine5Yaakov A. Levine6Pui Yan Chiu7Ping Wang8Sangeeta S. Chavan9Bruce T. Volpe10Barbara Sherry11Betty Diamond12Center for Autoimmune, Musculoskeletal and Hematopoietic Diseases, The Feinstein Institute for Medical Research, Manhasset, NY, United StatesCenter for Autoimmune, Musculoskeletal and Hematopoietic Diseases, The Feinstein Institute for Medical Research, Manhasset, NY, United StatesCenter for Autoimmune, Musculoskeletal and Hematopoietic Diseases, The Feinstein Institute for Medical Research, Manhasset, NY, United StatesCenter for Autoimmune, Musculoskeletal and Hematopoietic Diseases, The Feinstein Institute for Medical Research, Manhasset, NY, United StatesCenter for Immunology and Inflammation, The Feinstein Institute for Medical Research, Manhasset, NY, United StatesSetPoint Medical Corporation, Valencia, CA, United StatesCenter for Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, NY, United StatesCenter for Immunology and Inflammation, The Feinstein Institute for Medical Research, Manhasset, NY, United StatesCenter for Immunology and Inflammation, The Feinstein Institute for Medical Research, Manhasset, NY, United StatesCenter for Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, NY, United StatesCenter for Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, NY, United StatesCenter for Immunology and Inflammation, The Feinstein Institute for Medical Research, Manhasset, NY, United StatesCenter for Autoimmune, Musculoskeletal and Hematopoietic Diseases, The Feinstein Institute for Medical Research, Manhasset, NY, United StatesPatients surviving a septic episode exhibit persistent immune impairment and increased mortality due to enhanced vulnerability to infections. In the present study, using the cecal ligation and puncture (CLP) model of polymicrobial sepsis, we addressed the hypothesis that altered vagus nerve activity contributes to immune impairment in sepsis survivors. CLP-surviving mice exhibited less TNFα in serum following administration of LPS, a surrogate for an infectious challenge, than control-operated (control) mice. To evaluate the role of the vagus nerve in the diminished response to LPS, mice were subjected to bilateral subdiaphragmatic vagotomy at 2 weeks post-CLP. CLP-surviving vagotomized mice exhibited increased serum and tissue TNFα levels in response to LPS-challenge compared to CLP-surviving, non-vagotomized mice. Moreover, vagus nerve stimulation in control mice diminished the LPS-induced TNFα responses while having no effect in CLP mice, suggesting constitutive activation of vagus nerve signaling in CLP-survivors. The percentage of splenic CD4+ ChAT-EGFP+ T cells that relay vagus signals to macrophages was increased in CLP-survivors compared to control mice, and vagotomy in CLP-survivors resulted in a reduced percentage of ChAT-EGFP+ cells. Moreover, CD4 knockout CLP-surviving mice exhibited an enhanced LPS-induced TNFα response compared to wild-type mice, supporting a functional role for CD4+ ChAT+ T cells in mediating inhibition of LPS-induced TNFα responses in CLP-survivors. Blockade of the cholinergic anti-inflammatory pathway with methyllcaconitine, an α7 nicotinic acetylcholine receptor antagonist, restored LPS-induced TNFα responses in CLP-survivors. Our study demonstrates that the vagus nerve is constitutively active in CLP-survivors and contributes to the immune impairment.https://www.frontiersin.org/article/10.3389/fimmu.2018.02032/fullinnate immune responsesepsis survivorsvagus tonic activityCD4+ ChAT+ T cellTNFα |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Minakshi Rana Yurong Fei-Bloom Myoungsun Son Andrea La Bella Mahendar Ochani Yaakov A. Levine Yaakov A. Levine Pui Yan Chiu Ping Wang Sangeeta S. Chavan Bruce T. Volpe Barbara Sherry Betty Diamond |
spellingShingle |
Minakshi Rana Yurong Fei-Bloom Myoungsun Son Andrea La Bella Mahendar Ochani Yaakov A. Levine Yaakov A. Levine Pui Yan Chiu Ping Wang Sangeeta S. Chavan Bruce T. Volpe Barbara Sherry Betty Diamond Constitutive Vagus Nerve Activation Modulates Immune Suppression in Sepsis Survivors Frontiers in Immunology innate immune response sepsis survivors vagus tonic activity CD4+ ChAT+ T cell TNFα |
author_facet |
Minakshi Rana Yurong Fei-Bloom Myoungsun Son Andrea La Bella Mahendar Ochani Yaakov A. Levine Yaakov A. Levine Pui Yan Chiu Ping Wang Sangeeta S. Chavan Bruce T. Volpe Barbara Sherry Betty Diamond |
author_sort |
Minakshi Rana |
title |
Constitutive Vagus Nerve Activation Modulates Immune Suppression in Sepsis Survivors |
title_short |
Constitutive Vagus Nerve Activation Modulates Immune Suppression in Sepsis Survivors |
title_full |
Constitutive Vagus Nerve Activation Modulates Immune Suppression in Sepsis Survivors |
title_fullStr |
Constitutive Vagus Nerve Activation Modulates Immune Suppression in Sepsis Survivors |
title_full_unstemmed |
Constitutive Vagus Nerve Activation Modulates Immune Suppression in Sepsis Survivors |
title_sort |
constitutive vagus nerve activation modulates immune suppression in sepsis survivors |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Immunology |
issn |
1664-3224 |
publishDate |
2018-09-01 |
description |
Patients surviving a septic episode exhibit persistent immune impairment and increased mortality due to enhanced vulnerability to infections. In the present study, using the cecal ligation and puncture (CLP) model of polymicrobial sepsis, we addressed the hypothesis that altered vagus nerve activity contributes to immune impairment in sepsis survivors. CLP-surviving mice exhibited less TNFα in serum following administration of LPS, a surrogate for an infectious challenge, than control-operated (control) mice. To evaluate the role of the vagus nerve in the diminished response to LPS, mice were subjected to bilateral subdiaphragmatic vagotomy at 2 weeks post-CLP. CLP-surviving vagotomized mice exhibited increased serum and tissue TNFα levels in response to LPS-challenge compared to CLP-surviving, non-vagotomized mice. Moreover, vagus nerve stimulation in control mice diminished the LPS-induced TNFα responses while having no effect in CLP mice, suggesting constitutive activation of vagus nerve signaling in CLP-survivors. The percentage of splenic CD4+ ChAT-EGFP+ T cells that relay vagus signals to macrophages was increased in CLP-survivors compared to control mice, and vagotomy in CLP-survivors resulted in a reduced percentage of ChAT-EGFP+ cells. Moreover, CD4 knockout CLP-surviving mice exhibited an enhanced LPS-induced TNFα response compared to wild-type mice, supporting a functional role for CD4+ ChAT+ T cells in mediating inhibition of LPS-induced TNFα responses in CLP-survivors. Blockade of the cholinergic anti-inflammatory pathway with methyllcaconitine, an α7 nicotinic acetylcholine receptor antagonist, restored LPS-induced TNFα responses in CLP-survivors. Our study demonstrates that the vagus nerve is constitutively active in CLP-survivors and contributes to the immune impairment. |
topic |
innate immune response sepsis survivors vagus tonic activity CD4+ ChAT+ T cell TNFα |
url |
https://www.frontiersin.org/article/10.3389/fimmu.2018.02032/full |
work_keys_str_mv |
AT minakshirana constitutivevagusnerveactivationmodulatesimmunesuppressioninsepsissurvivors AT yurongfeibloom constitutivevagusnerveactivationmodulatesimmunesuppressioninsepsissurvivors AT myoungsunson constitutivevagusnerveactivationmodulatesimmunesuppressioninsepsissurvivors AT andrealabella constitutivevagusnerveactivationmodulatesimmunesuppressioninsepsissurvivors AT mahendarochani constitutivevagusnerveactivationmodulatesimmunesuppressioninsepsissurvivors AT yaakovalevine constitutivevagusnerveactivationmodulatesimmunesuppressioninsepsissurvivors AT yaakovalevine constitutivevagusnerveactivationmodulatesimmunesuppressioninsepsissurvivors AT puiyanchiu constitutivevagusnerveactivationmodulatesimmunesuppressioninsepsissurvivors AT pingwang constitutivevagusnerveactivationmodulatesimmunesuppressioninsepsissurvivors AT sangeetaschavan constitutivevagusnerveactivationmodulatesimmunesuppressioninsepsissurvivors AT brucetvolpe constitutivevagusnerveactivationmodulatesimmunesuppressioninsepsissurvivors AT barbarasherry constitutivevagusnerveactivationmodulatesimmunesuppressioninsepsissurvivors AT bettydiamond constitutivevagusnerveactivationmodulatesimmunesuppressioninsepsissurvivors |
_version_ |
1725741292458082304 |