The Role of Acetylcholine in the Inflammatory Response in Animals Surviving Sepsis Induced by Cecal Ligation and Puncture

Abstract

The cholinergic anti-inflammatory pathway controls the inflammatory response and nonreflexive consciousness through bidirectional communication between the brain and immune system. Moreover, brain acetylcholinesterase activity may have a role in regulating the vagus nerve in this pathway. Thus, we analyzed the role of acetylcholine (ACh) in the inflammatory response 15 days after induction of sepsis by cecal ligation and puncture (CLP). Balb/c mice were pretreated with or without donepezil (5 mg/kg/day, orally) 7 days before CLP, and mice homozygous for vesicular ACh transporter (VAChT) knockdown (KD) were subjected to CLP. All animals were sacrificed 15 days after CLP, and the plasma, spleen, and hippocampus were collected. Characterization of splenic lymphocytes and cytokine levels in the plasma, spleen, and hippocampus was determined. Our results showed a splenomegaly in group CLP. The numbers of cytotoxic T cells, helper T cells, regulatory T cells, B cells, and Th17 cells differed between mice subjected to CLP and to sham operation in both untreated and donepezil-treated groups. In VAChT-KD mice, CLP resulted in decreased cytotoxic and helper T cells and increased in Th17 cells compared with the sham. Additionally, in VAChT-KD mice, the levels of pro-inflammatory cytokines, such as IL-1β, IL-6, and TNF-α, were increased following CLP. Thus, we concluded that ACh affected the inflammatory response at 15 days after CLP since stimulation of cholinergic transmission increased the proliferation of lymphocytes, including regulatory T cells, in association with a lower inflammatory profile and VAChT-KD decreased the number of lymphocytes and increased inflammation.

Acute lung injury is reduced by the α7nAChR agonist PNU‐282987 through changes in the macrophage profile

“…In addition, recent work from our group demonstrated that VAChT expression levels, which directly modulate the levels of acetylcholine release (44), control lung inflammation in mice (19). Also, Jeremias et al (45) showed that VAChT modulates levels of cytokines released in lung in a model of cecal ligation and punctureinduced sepsis. Moreover, increasing evidence indicates that activation of a7nAChR can be protective in a variety of inflammatory diseases including ALI (18,29,46).…”

“…Also, Jeremias et al . (45) showed that VAChT modulates levels of cytokines released in lung in a model of cecal ligation and puncture‐ induced sepsis. Moreover, increasing evidence indicates that activation of α7nAChR can be protective in a variety of inflammatory diseases including ALI (18, 29, 46).…”

Regulation of Sirtuin 3-Mediated Deacetylation of Cyclophilin D Attenuated Cognitive Dysfunction Induced by Sepsis-Associated Encephalopathy in Mice

“…Elevated levels of cytokines, such as IL-1β, TNF-α, and IL-6, have been observed in the brain parenchyma and cerebrospinal fluid after sepsis (Jeremias et al 2015 ; Takahashi et al 2014 ). The neuropathology in SAE is quite similar to that in patients with severe sepsis in terms of elevated levels of proinflammatory cytokines in the brain (Blom et al 2015 ).…”

Protective Effect of Dexmedetomidine on Acute Lung Injury via the Upregulation of Tumour Necrosis Factor-α-Induced Protein-8-like 2 in Septic Mice

“…Immediately after the surgery, the mice were intraperitoneally injected Dex (50 μg/kg) or the same volume (200 μl) of vehicles PBS. After that, the mice were injected subcutaneously with 1 ml of sterile saline for resuscitation and put into an incubator until they recovered from the anaesthesia [19,20].…”