Cholinergic anti‐inflammatory pathway in the non‐obese diabetic mouse model

Koopman, Frieda A.; Vosters, Jelle L.; Roescher, Nienke; Broekstra, Niels; Tak, Paul P.; Vervoordeldonk, Margriet J.

doi:10.1111/odi.12354

Cited by 11 publications

(7 citation statements)

References 29 publications

(39 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Because the ␤-cell-specific KO of Chrm3 (encoding M 3 R) in mice shows no BCM phenotype (20), this functionally important and highly expressed muscarinic AChR is unlikely to play a role in ␤-cell survival. However, preclinical studies have established that nicotine administration (21) or nonspecific pharmacologic cholinergic stimulation can reverse the development or prevent T1D (22,35) and T2D (23). Our aim in the current study was to test whether specific agonists activating the ␣7R, a ligand-gated ion channel with a well-defined role in the cholinergic anti-inflammatory pathway, might provide protection from mouse T1D development and to examine how the ␤-cell ␣7R might contribute to this improvement.…”

Section: Discussionmentioning

confidence: 99%

β-Cell mass restoration by α7 nicotinic acetylcholine receptor activation

Gupta

Lacayo

Greene

et al. 2018

Journal of Biological Chemistry

View full text Add to dashboard Cite

Edited by Jeffrey E. PessinAlthough it is well-established how nutrients, growth factors, and hormones impact functional ␤-cell mass (BCM), the influence of the central nervous system in this regard, and especially in the context of islet immune modulation, has been understudied. Here we investigated the expression and activity of pancreatic islet ␣7 nicotinic acetylcholine receptor (␣7nAChR) in islet anti-inflammatory and prosurvival signaling. Systemic administration of ␣7nAChR agonists in mice improved glucose tolerance and curtailed streptozotocin-induced hyperglycemia by retaining BCM, in part through maintaining Pdx1 and MafA expression and reducing apoptosis. ␣7nAChR activation of mouse islets ex vivo led to reduced inflammatory drive through a JAK2-STAT3 pathway that couples with CREB/Irs2/Akt survival signaling. Because the vagus nerve conveys anti-inflammatory signals to immune cells of the spleen and other nonneural tissues in the viscera by activating ␣7nAChR agonists, our study suggests a novel role for ␤-cell ␣7nAChR that functions to maintain ␤-cell survival and mass homeostasis through modulating islet cytokine and phosphatidylinositol 3-kinase-dependent signaling pathways. Exploiting these pathways may have therapeutic potential for the treatment of autoimmune diabetes. element-binding protein.; Veh, vehicle; i.p., intraperitoneal; IPGTT, intraperitoneal glucose tolerance test; TUNEL, deoxynucleotidyltransferase-mediated dUTP nick end labeling. Reagents for ␣7nAChR manipulationThe partial agonist GTS-21 (Tocris Bioscience) and the specific agonist PNU-282987 (Alomone Labs) were used for ␣7R activation, whereas MLA (Tocris) was used as a specific ␣7R ␣7nAChR agonists preserve ␤-cell mass

show abstract

Section: Discussionmentioning

confidence: 99%

β-Cell mass restoration by α7 nicotinic acetylcholine receptor activation

Gupta

Lacayo

Greene

et al. 2018

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Activation of the CAP can be achieved by vagus nerve stimulation or cholinergic agonists [ 16 ]. 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

View full text Add to dashboard Cite

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.

show abstract

“…10 Furthermore, in various animal models of inflammation, the α7nAChR agonists (GTS-21, nicotine and AR-R17779) stimulate α7nAChRs to elicit activation of CAP resulting in alleviated disease activity. 5,8,11,12 Also, α-bgt and methyllycaconitine (specific α7nAChR antagonists) can block α7 receptors and deactivate the anti-inflammatory effect of the CAP in several inflammations. 12,13 In addition, knockdown of α7nAChR in mice with experimental arthritis increases production of proinflammatory cytokines, aggravates synovial inflammation and suppress the adaptive immunity by decreasing proliferative immune response.…”

Section: The Cholinergic Anti-inflammatory Pathwaymentioning

confidence: 99%

“…In models of collagen‐induced arthritis and adjuvant‐induced arthritis, electrical stimulation of the vagus nerve slowed down the progression of the diseases, while vagotomy surgery exacerbated symptoms and hyperalgesia by enhancing the neutrophil migration 10 . Furthermore, in various animal models of inflammation, the α7nAChR agonists (GTS‐21, nicotine and AR‐R17779) stimulate α7nAChRs to elicit activation of CAP resulting in alleviated disease activity 5,8,11,12 . Also, α‐bgt and methyllycaconitine (specific α7nAChR antagonists) can block α7 receptors and deactivate the anti‐inflammatory effect of the CAP in several inflammations 12,13 .…”

Section: Introductionmentioning

confidence: 99%

The role of the cholinergic anti‐inflammatory pathway in autoimmune rheumatic diseases

et al. 2021

Scand J Immunol

View full text Add to dashboard Cite

The cholinergic anti-inflammatory pathway (CAP) is a classic neuroimmune pathway, consisting of the vagus nerve, acetylcholine (ACh)-the pivotal neurotransmitter of the vagus nerve-and its receptors. This pathway can activate and regulate the activities of immune cells, inhibit cell proliferation and differentiation, as well as suppress cytokine release, thereby playing an anti-inflammatory role, and widely involved in the occurrence and development of various diseases; recent studies have demonstrated that the CAP may be a new target for the treatment of autoimmune rheumatic diseases. In this review, we will summarize the latest progress with the view of figuring out the role of the cholinergic pathway and how it interacts with inflammatory reactions in several autoimmune rheumatic diseases, and many advances are results from a wide range of experiments performed in vitro and in vivo.How to cite this article: Lv J, Ji X, Li Z, Hao H. The role of the cholinergic anti-inflammatory pathway in autoimmune rheumatic diseases.

show abstract

Cholinergic anti‐inflammatory pathway in the non‐obese diabetic mouse model

Abstract: Intervention of the CAP in NOD mice leads to minimal changes in inflammatory cytokines, but did not affect overall inflammation and function of SG or development of diabetes.

Cited by 11 publications

References 29 publications

β-Cell mass restoration by α7 nicotinic acetylcholine receptor activation

β-Cell mass restoration by α7 nicotinic acetylcholine receptor activation

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

The role of the cholinergic anti‐inflammatory pathway in autoimmune rheumatic diseases

Contact Info

Product

Resources

About