Constitutive Vagus Nerve Activation Modulates Immune Suppression in Sepsis Survivors

Abstract

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.

Follicular dendritic cell dysfunction contributes to impaired antigen-specific humoral responses in sepsis-surviving mice

“…We therefore measured the expression of AID in NP-specific GC B cells. We have shown that CLP mice exhibit reduced serum TNF-α compared with sham mice when challenged with LPS (30). Previous studies suggest that AID expression is inducible and can be regulated by TNF-α in an NF-κB-dependent manner (31).…”

Sepsis-associated encephalopathy: a vicious cycle of immunosuppression

“…In addition, the CAP is recognized as a neuroprotective mechanism that is capable of reducing both systemic and cerebral inflammation, which further attenuates brain damage after activation [118,119]. Intriguingly, the vagus nerve is constitutively activated in septic survivors and appears to be associated with immune impairment and increased vulnerability to infections [120]. Therefore, the bidirectional changes in CAP activity deserve timely recognition and interference to eliminate potential hazards of the immune response.…”

“…The failure of efficient neuromodulation can lead to uncontrolled inflammation and irreversible damage to the central nervous system. Reconstruction of either HPA axis or CAP through administration of corticosteroids or stimulation of vagus efferent nerve, respectively, show great benefits for septic animals by ameliorating multiple organ damage and improving the survival [62,120]. In fact, deteriorative neuroinflammation is the center of the vicious cycle of SAE and immunosuppression because it arises from the aberrant response of immune system and acts as a key contributor to brain dysfunction.…”

Solitary chemosensory cells are innervated by trigeminal nerve endings and autoregulated by cholinergic receptors

“…In a recent mouse study assessing the role of cholinergic innervation on inflammation, utilizing the cecal ligation puncture model, subdiaphragmatic vagotomy abolished immunosuppression noted in nonvagotomized mice. 27 The conclusion of the study was that cholinergic tone determines the immune balance, shifting between enhanced vagal nerve activation leading to an immunosuppressed phenotype and decreased vagal tone leading to inflammation. 27 Thus, the lack of innervation of nasal polyps, as noted in our study, may generate a pro‐inflammatory state by allowing for unchecked SCC expansion with a feed‐forward cycle of IL‐25 production.…”