The Protective Effect of Alpha 7 Nicotinic Acetylcholine Receptor Activation on Critical Illness and Its Mechanism

Ren, Chao; Tong, Yalin; Li, Juncong; Lu, Zhongqiu; Yao, Yong‐Ming

doi:10.7150/ijbs.16404

Cited by 59 publications

(40 citation statements)

References 133 publications

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“…The dorsal motor nucleus is activated after interconnecting with nucleus tractus solitarius, and further drives the excitation of efferent vagus nerve for Ach release [102,103]. The anti-inflammatory effects of CAP are achieved after activation of α7nAchR, which disrupts activation of NF-κB and inflammasomes by promoting phosphorylation of the Janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3) pathway, inhibiting the TLR4-myeloid differentiation factor 88 (MyD88)-interleukin-1 receptorassociated kinase (IRAK) cascade and the release of mitochondrial DNA [104][105][106][107]. It has been reported that activation of α7nAchR is capable of blocking activation and entry of NF-κB via interfering phosphorylation of inhibitor κB (IκB) [108,109].…”

Section: Cholinergic Anti-inflammatory Pathwaymentioning

confidence: 99%

Sepsis-associated encephalopathy: a vicious cycle of immunosuppression

Ren

Yao

Zhang

et al. 2020

J Neuroinflammation

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Sepsis-associated encephalopathy (SAE) is commonly complicated by septic conditions, and is responsible for increased mortality and poor outcomes in septic patients. Uncontrolled neuroinflammation and ischemic injury are major contributors to brain dysfunction, which arises from intractable immune malfunction and the collapse of neuroendocrine immune networks, such as the cholinergic anti-inflammatory pathway, hypothalamic-pituitaryadrenal axis, and sympathetic nervous system. Dysfunction in these neuromodulatory mechanisms compromised by SAE jeopardizes systemic immune responses, including those of neutrophils, macrophages/monocytes, dendritic cells, and T lymphocytes, which ultimately results in a vicious cycle between brain injury and a progressively aberrant immune response. Deep insight into the crosstalk between SAE and peripheral immunity is of great importance in extending the knowledge of the pathogenesis and development of sepsis-induced immunosuppression, as well as in exploring its effective remedies.

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Section: Cholinergic Anti-inflammatory Pathwaymentioning

confidence: 99%

Sepsis-associated encephalopathy: a vicious cycle of immunosuppression

Ren

Yao

Zhang

et al. 2020

J Neuroinflammation

Self Cite

156

131

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“…GTS-21, a classic cholinergic agonist, can bind to the α7 subunit of the nicotinic acetylcholine receptor (α7nAChR) of inflammatory cells to induce an anti-inflammatory response [ 17 ]. A previous study showed that the CAP is involved in the reduction of inflammation in experimental sepsis, acute lung injury, ischemia/reperfusion injury, and pancreatitis [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

The effect of the cholinergic anti-inflammatory pathway on collagen-induced arthritis involves the modulation of dendritic cell differentiation

Liu

Luo

et al. 2018

Arthritis Res Ther

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BackgroundThe cholinergic anti-inflammatory pathway (CAP) has a strong anti-inflammatory effect on collagen-induced arthritis (CIA), a classic animal model of rheumatoid arthritis (RA). However, the underlying immune regulatory mechanism remains unclear. Here, we investigated the effect of the CAP on arthritis development and the involvement of dendritic cells (DCs).MethodsForty DBA/1 mice were randomly divided into five groups: a control group (sham vagotomy+ phosphate-buffered saline; shamVGX+PBS), a CIA group (shamVGX+CIA + PBS), a vagotomy group (VGX + CIA + PBS), a GTS-21 (4 mg/kg) group (shamVGX+CIA + GTS-4), and a GTS-21 (8 mg/kg) group (shamVGX+CIA + GTS-8). The vagotomy group underwent left cervical vagotomy 4 days before arthritis induction, whereas the sham-vagotomy group underwent vagus nerve exposure. Mice were pretreated with GTS-21 by intraperitoneal injection on the day of surgery. The degree of arthritis was measured by using the arthritis score, hematoxylin and eosin staining, and TRAP (tartrate-resistant acid phosphatase) staining. Flow cytometry was used to detect the expression of CD80 and major histocompatibility complex II (MHC II) on CD11c+ DCs in the spleen. Luminex was used to detect the serum concentration of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNFα), and IL-10. Immunohistochemistry was used to detect CD11c expression in the synovium. The effects of GTS-21 on DC differentiation and maturation were examined in vitro by treating bone marrow–derived DCs with GTS-21 and assessing differentiation and maturation. Flow cytometry was used to analyze CD80 and MHC II expression on the surface of DCs.ResultsGTS-21 treatment ameliorated clinical arthritis in a mouse model of CIA in vivo, decreasing the secretion of pro-inflammatory cytokines in the serum and downregulating CD80 and MHC II expression on DCs in the spleen of CIA mice. GTS-21 treatment strongly suppressed the infiltration of DCs into the synovium. Vagotomy itself did not exacerbate the severity of arthritis in CIA mice. In vitro, GTS-21 (10 μmol/L) significantly downregulated CD80 and MHC II in bone marrow–derived immature DCs and this effect was blocked by the α7-nicotinic acetylcholine receptor antagonist methyllycaconitine (MLA). However, GTS-21 had no effects on mature DCs.ConclusionsThe present study provides new insight into the mechanism underlying the effects of the CAP on RA and indicates that the immunosuppressive effect of GTS-21 may be mediated by the inhibition of DC differentiation.Electronic supplementary materialThe online version of this article (10.1186/s13075-018-1759-9) contains supplementary material, which is available to authorized users.

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“…In this context, it has been shown that acetylcholine (ACh) released from nerve fibers may have anti-inflammatory effects inasmuch as it suppresses cells of the immune system through activation of α7 nicotinic acetylcholine receptor (α7nAChR). In fact, stimulation of α7nAChR activates intracellular signaling pathways that culminate in the inhibition of NF-kβ factor in immune cells, thereby suppressing the release of proinflammatory cytokines 13,14 . This mechanism has been referred to in the literature as "cholinergic anti-inflammatory pathway".…”

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confidence: 99%

Rivastigmine prevents injury induced by ischemia and reperfusion in rat liver

et al. 2018

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Purpose: To evaluate whether pre-treatment with rivastigmine is able to attenuate the I/R induced lesions in rat liver. Methods: SHAM animals or those submitted to I/R, non-treated or pre-treated with rivastigminine (2mg/kg) either 50 or 15 minutes before ischemia, were used. After I/R protocol, these animals were killed and their livers were harvested to measurement of the mitochondrial swelling as well as the malondialdehyde (MDA), nitrite and nitrate tissue concentration. Blood was also harvested for serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) determinations. Results: I/R promoted a significant increase of mitochondrial swelling in the studied animals. This increase of mitochondrial swelling was partially prevented by rivastigmine, but only if administered 50 minutes before ischemia. No significant modification of MDA, nitrite or nitrate tissue concentrations was observed in consequence of I/R, followed or not by rivastigmine treatments. In addition, I/R elevated both AST and ALT. These elevations of serum enzymes were not reversed by the different rivastigmine treatments. Conclusions: Rivastigmine administered 50 minutes before ischemia attenuates I/R-induced mitochondrial swelling, that indicates liver injury. This protective effect may be related to a greater stimulation of α7nAChR present in the Kupffer cells by the non-methabolized ACh, leading to an attenuation of I/R-induced inflammation.

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The Protective Effect of Alpha 7 Nicotinic Acetylcholine Receptor Activation on Critical Illness and Its Mechanism

Cited by 59 publications

References 133 publications

Sepsis-associated encephalopathy: a vicious cycle of immunosuppression

Sepsis-associated encephalopathy: a vicious cycle of immunosuppression

The effect of the cholinergic anti-inflammatory pathway on collagen-induced arthritis involves the modulation of dendritic cell differentiation

Rivastigmine prevents injury induced by ischemia and reperfusion in rat liver

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