scholarly journals Cholinergic Modulation of the Immune System in Neuroinflammatory Diseases

Diseases ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 29
Author(s):  
Marcella Reale ◽  
Erica Costantini
Keyword(s):  
Immune Cells ◽  
Disease Process ◽  
Inflammatory Pathway ◽  
Nervous Systems ◽  
Α7 Nachr ◽  
Cholinergic Signaling ◽  
Central Nervous Systems ◽  
Anti Inflammatory ◽  
Peripheral Immune Cells ◽  
Brain Acetylcholine

Frequent diseases of the CNS, such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and psychiatric disorders (e.g., schizophrenia), elicit a neuroinflammatory response that contributes to the neurodegenerative disease process itself. The immune and nervous systems use the same mediators, receptors, and cells to regulate the immune and nervous systems as well as neuro-immune interactions. In various neurodegenerative diseases, peripheral inflammatory mediators and infiltrating immune cells from the periphery cause exacerbation to current injury in the brain. Acetylcholine (ACh) plays a crucial role in the peripheral and central nervous systems, in fact, other than cells of the CNS, the peripheral immune cells also possess a cholinergic system. The findings on peripheral cholinergic signaling, and the activation of the “cholinergic anti-inflammatory pathway” mediated by ACh binding to α7 nAChR as one of the possible mechanisms for controlling inflammation, have restarted interest in cholinergic-mediated pathological processes and in the new potential therapeutic target for neuro-inflammatory-degenerative diseases. Herein, we focus on recent progress in the modulatory mechanisms of the cholinergic anti-inflammatory pathway in neuroinflammatory diseases.

The Role of α7nAChR-Mediated Cholinergic Anti-inflammatory Pathway in Immune Cells

Inflammation ◽  
2021 ◽  
Author(s):  
Yi-jin Wu ◽  
Li Wang ◽  
Chao-fan Ji ◽  
Shao-fei Gu ◽  
Qin Yin ◽  
...  
Keyword(s):  
Immune Cells ◽  
Inflammatory Pathway ◽  
Anti Inflammatory

scholarly journals Systemic Administration of α7-Nicotinic Acetylcholine Receptor Ligands Does Not Improve Renal Injury or Behavior in Mice With Advanced Systemic Lupus Erythematosus

2021 ◽  
Vol 8 ◽  
Author(s):  
Jessica Y. Morales ◽  
Cassandra M. Young-Stubbs ◽  
Caroline G. Shimoura ◽  
William R. Kem ◽  
Victor V. Uteshev ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Nicotinic Acetylcholine Receptor ◽  
Lupus Erythematosus ◽  
Advanced Disease ◽  
Organ Damage ◽  
Systemic Lupus ◽  
Nicotinic Acetylcholine ◽  
Inflammatory Pathway ◽  
Α7 Nachr ◽  
Anti Inflammatory

There is a critical need for safe treatment options to control inflammation in patients with systemic lupus erythematosus (SLE) since the inflammation contributes to morbidity and mortality in advanced disease. Endogenous neuroimmune mechanisms like the cholinergic anti-inflammatory pathway can be targeted to modulate inflammation, but the ability to manipulate such pathways and reduce inflammation and end organ damage has not been fully explored in SLE. Positive allosteric modulators (PAM) are pharmacological agents that inhibit desensitization of the nicotinic acetylcholine receptor (α7-nAChR), the main anti-inflammatory feature within the cholinergic anti-inflammatory pathway, and may augment α7-dependent cholinergic tone to generate therapeutic benefits in SLE. In the current study, we hypothesize that activating the cholinergic anti-inflammatory pathway at the level of the α7-nAChR with systemic administration of a partial agonist, GTS-21, and a PAM, PNU-120596, would reduce inflammation, eliminating the associated end organ damage in a mouse model of SLE with advanced disease. Further, we hypothesize that systemic α7 ligands will have central effects and improve behavioral deficits in SLE mice. Female control (NZW) and SLE mice (NZBWF1) were administered GTS-21 or PNU-120596 subcutaneously via minipumps for 2 weeks. We found that the increased plasma dsDNA autoantibodies, splenic and renal inflammation, renal injury and hypertension usually observed in SLE mice with advanced disease at 35 weeks of age were not altered by GTS-21 or PNU-120596. The anxiety-like behavior presented in SLE mice was also not improved by GTS-21 or PNU-120596. Although no significant beneficial effects of α7 ligands were observed in SLE mice at this advanced stage, we predict that targeting this receptor earlier in the pathogenesis of the disease may prove to be efficacious and should be addressed in future studies.

Pharmacological influencing of cholinergic anti-inflammatory pathway in infectious diseases and inflammatory pathologies

2020 ◽  
Vol 20 ◽  
Author(s):  
Miroslav Pohanka
Keyword(s):  
Calcium Ions ◽  
Parasympathetic Nervous System ◽  
Α7 Nicotinic Acetylcholine Receptor ◽  
Nicotinic Acetylcholine ◽  
Inflammatory Pathway ◽  
Major Task ◽  
Α7 Nachr ◽  
Nuclear Factors ◽  
Anti Inflammatory ◽  
Pathway Regulation

: Cholinergic anti-inflammatory pathway is a part of parasympathetic nervous system and it can be also entitled as an anti-inflammatory reflex. It consists from terminations of vagal nerve into blood, acetylcholine released from the terminations, macrophages and other cells having α7 nicotinic acetylcholine receptor (α7 nAChR), calcium ions crossing through the receptor and interacting with nuclear factors, and erythrocytes with acetylcholinesterase (AChE) terminating the neurotransmission. Stopping of inflammatory cytokines production is the major task for the cholinergic antiinflammatory pathway. The pathway can be pharmacologically influenced by agonizing respective antagonizing on α7 nAChR or by inhibition of AChE. This review is focused on cholinergic anti-inflammatory pathway regulation by drugs. Compounds that inhibit cholinesterases like huperzine, rivastigmine, galantamine and distinguishing between types of inhibitors and impact on cholinergic anti-inflammatory pathway is discussed and survey of actual literature is provided.

scholarly journals COVID-19 and Cholinergic Anti-inflammatory Pathway: In silico Identification of an Interaction between α7 Nicotinic Acetylcholine Receptor and the Cryptic Epitopes of SARS-CoV and SARS-CoV-2 Spike Glycoproteins

2020 ◽  
Author(s):  
George Lagoumintzis ◽  
Christos T. Chasapis ◽  
Nikolaos Alexandris ◽  
Socrates Tzartos ◽  
Elias Eliopoulos ◽  
...  
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Molecular Model ◽  
Human Antibody ◽  
Protective Effects ◽  
Spike Glycoprotein ◽  
Α7 Nicotinic Acetylcholine Receptor ◽  
Nicotinic Acetylcholine ◽  
Inflammatory Pathway ◽  
Α7 Nachr ◽  
Anti Inflammatory

ABSTRACTSARS-CoV-2 is the coronavirus that originated in Wuhan in December 2019 and has spread globally. The observation of a low prevalence of smokers among hospitalized COVID-19 patients has led to the development of a hypothesis that nicotine could have protective effects by enhancing the cholinergic anti-inflammatory pathway. Based on clinical data and on modelling and docking experiments we have previously presented the potential interaction between SARS-CoV-2 Spike glycoprotein and nicotinic acetylcholine receptors (nAChRs), due to a “toxin-like” epitope on the Spike Glycoprotein, with homology to a sequence of a snake venom toxin. We here present that this epitope coincides with the well-described cryptic epitope for the human antibody CR3022 and with the epitope for the recently described COVA1-16 antibody. Both antibodies are recognizing neighboring epitopes, are not interfering with the ACE2 protein and are not able to inhibit SARS-CoV and SARS-CoV-2 infections. In this study we present the molecular complexes of both SARS-CoV and SARS-CoV-2 Spike Glycoproteins, at their open or closed conformations, with the molecular model of the human α7 nAChR. We found that the interface of all studied protein complexes involves a large part of the “toxin-like” sequences of SARS-CoV and SARS-CoV-2 Spike glycoproteins and toxin binding site of human α7 nAChR.

scholarly journals Microbial Infections Are a Risk Factor for Neurodegenerative Diseases

2021 ◽  
Vol 15 ◽  
Author(s):  
Sarah K. Lotz ◽  
Britanie M. Blackhurst ◽  
Katie L. Reagin ◽  
Kristen E. Funk
Keyword(s):  
Nervous System ◽  
Neurodegenerative Diseases ◽  
Immune Cells ◽  
Disease Process ◽  
Cellular Mechanisms ◽  
Microbial Infections ◽  
The Central Nervous System ◽  
Nervous System Function ◽  
Peripheral Immune Cells

Neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis, comprise a family of disorders characterized by progressive loss of nervous system function. Neuroinflammation is increasingly recognized to be associated with many neurodegenerative diseases but whether it is a cause or consequence of the disease process is unclear. Of growing interest is the role of microbial infections in inciting degenerative neuroinflammatory responses and genetic factors that may regulate those responses. Microbial infections cause inflammation within the central nervous system through activation of brain-resident immune cells and infiltration of peripheral immune cells. These responses are necessary to protect the brain from lethal infections but may also induce neuropathological changes that lead to neurodegeneration. This review discusses the molecular and cellular mechanisms through which microbial infections may increase susceptibility to neurodegenerative diseases. Elucidating these mechanisms is critical for developing targeted therapeutic approaches that prevent the onset and slow the progression of neurodegenerative diseases.

scholarly journals FGF21 alleviates neuroinflammation following ischemic stroke by modulating the temporal and spatial dynamics of microglia/macrophages

2020 ◽  
Author(s):  
Dongxue Wang ◽  
Fei Liu ◽  
Liyun Zhu ◽  
Ping Lin ◽  
Fanyi Han ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Immune Cells ◽  
Cell Sorting ◽  
Critical Role ◽  
Experimental Stroke ◽  
Fibroblast Growth Factor 21 ◽  
Ppar Γ ◽  
Promising Therapeutic Approach ◽  
Anti Inflammatory ◽  
Peripheral Immune Cells

Abstract Background: Resident microglia and macrophages are the predominant contributors to neuroinflammation and immune reactions, which play a critical role in the pathogenesis of ischemic brain injury. Controlling inflammatory responses is considered a promising therapeutic approach for stroke. Recombinant human fibroblast growth factor 21 (rhFGF21) has anti-inflammatory properties by modulating microglia and macrophages, but our knowledge of the inflammatory modulation of rhFGF21 in focal cerebral ischemia is lacking. Therefore, we investigated whether rhFGF21 improves ischemic outcomes in experimental stroke by targeting microglia and macrophages. Methods: C57BL/6 mice were subjected to transient middle cerebral artery occlusion (tMCAO) and randomly divided into groups that received intraperitoneal rhFGF21 or vehicle daily starting at 6 h after reperfusion. Behavior assessments were monitored for 14 d after tMACO and the gene expression levels of inflammatory cytokines were analyzed with qPCR. The phenotypic variation of microglia/macrophages and the presence of infiltrated immune cells were examined by flow cytometry and immunostaining. Additionally, magnetic cell sorting (MACS) in combination with fluorescence-activated cell sorting (FACS) was used to purify microglia and macrophages. Results: rhFGF21 administration ameliorated neurological deficits in behavioral tests by regulating the secretion of pro-inflammatory and anti-inflammatory cytokines. rhFGF21 also attenuated the polarization of microglia/macrophages toward the M1 phenotype and the accumulation of peripheral immune cells after stroke, accompanied by a temporal evolution of the phenotype of microglia/macrophages and infiltration of peripheral immune cells. Furthermore, rhFGF21 treatment through its actions on FGF receptor 1(FGFR1) inhibited M1 polarization of microglia and pro-inflammatory cytokine expression by suppressing nuclear factor-kappa B (NF-κB ) and upregulating peroxisome proliferator-activated receptor PPAR-γ. conclusion： In summary, rhFGF21 treatment promoted functional recovery in experimental stroke by modulating microglia/macrophage-mediated neuroinflammation via the NF-κB and PPAR-γ signaling pathways, making it a potential anti-inflammatory agent for stroke treatment.

scholarly journals Activation of the Cholinergic Anti-inflammatory Pathway Attenuated Angiotension II-Dependent Hypertension and Renal Injury

2021 ◽  
Vol 12 ◽  
Author(s):  
Shu-jie Wu ◽  
Zhe-wei Shi ◽  
Xue Wang ◽  
Fang-fang Ren ◽  
Zuo-yi Xie ◽  
...  
Keyword(s):  
Renal Fibrosis ◽  
Epithelial Mesenchymal Transition ◽  
Inflammatory Responses ◽  
Autonomic Control ◽  
Inflammatory Pathway ◽  
Mesenchymal Transition ◽  
Matrix Deposition ◽  
Α7 Nachr ◽  
Induced Hypertension ◽  
Anti Inflammatory

Background: Angiotensin II (AngII) induces renal fibrosis, characterized by fibroblast proliferation, inflammatory cell infiltration and excessive extracellular matrix deposition, all of which was relevant closely to hypertension. The vagus nerve-related cholinergic anti-inflammatory pathway (CAP) modulates local and systemic inflammatory responses. The aim of present study was to determine the effect of CAP on renal inflammation and fibrosis.Methods and Results: AngII-induced hypertension was induced in vivo by 14-days low-dose AngII infusion from osmotic minipumps. We used GTS-21 dihydrochloride, a selective nicotinic acetylcholine receptor agonist. Daily intraperitoneal GTS-21 injection and/or vagotomy started after hypertension was confirmed and continued for 4 weeks. The elevated blood pressure caused by AngII was significantly attenuated by GTS-21. Improved baroreflex sensitivity was observed after GTS-21 administration. Masson stain and immunoblotting revealed that deposition of excessive fibrosis and overexpression of inflammatory cytokines induced by AngII was reduced by GTS-21. To determine the role of autonomic control in CAP, unilateral vagotomy was performed. Vagotomy weakened the effect of CAP on AngII-induced hypertension. In vitro, GTS-21 suppressed NF-κB activation, attenuated AngII-induced epithelial-mesenchymal transition and reduced inflammation and fibrosis in NRK-52E cells; α-bungarotoxin (α-Bgt, an α7-nAChR selective antagonist) partly inhibited these effects.Conclusion: CAP protected against AngII-induced hypertension via improvement in autonomic control, suppression of NF-κB activation, and reduction of renal fibrosis and inflammatory response.

scholarly journals FGF21 alleviates neuroinflammation following ischemic stroke by modulating the temporal and spatial dynamics of microglia/macrophages

2020 ◽  
Author(s):  
Dongxue Wang ◽  
Fei Liu ◽  
Liyun Zhu ◽  
Ping Lin ◽  
Fanyi Han ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Immune Cells ◽  
Cell Sorting ◽  
Critical Role ◽  
Experimental Stroke ◽  
Fibroblast Growth Factor 21 ◽  
Ppar Γ ◽  
Promising Therapeutic Approach ◽  
Anti Inflammatory ◽  
Peripheral Immune Cells

Abstract Background: Resident microglia and macrophages are the predominant contributors to neuroinflammation and immune reactions, which play a critical role in the pathogenesis of ischemic brain injury. Controlling inflammatory responses is considered a promising therapeutic approach for stroke. Recombinant human fibroblast growth factor 21 (rhFGF21) has anti-inflammatory properties by modulating microglia and macrophages, but our knowledge of the inflammatory modulation of rhFGF21 in focal cerebral ischemia is lacking. Therefore, we investigated whether rhFGF21 improves ischemic outcomes in experimental stroke by targeting microglia and macrophages. Methods: C57BL/6 mice were subjected to transient middle cerebral artery occlusion (tMCAO) and randomly divided into groups that received intraperitoneal rhFGF21 or vehicle daily starting at 6 h after reperfusion. Behavior assessments were monitored for 14 d after tMACO and the gene expression levels of inflammatory cytokines were analyzed with qPCR. The phenotypic variation of microglia/macrophages and the presence of infiltrated immune cells were examined by flow cytometry and immunostaining. Additionally, magnetic cell sorting (MACS) in combination with fluorescence-activated cell sorting (FACS) was used to purify microglia and macrophages. Results: rhFGF21 administration ameliorated neurological deficits in behavioral tests by regulating the secretion of pro-inflammatory and anti-inflammatory cytokines. rhFGF21 also attenuated the polarization of microglia/macrophages toward the M1 phenotype and the accumulation of peripheral immune cells after stroke, accompanied by a temporal evolution of the phenotype of microglia/macrophages and infiltration of peripheral immune cells. Furthermore, rhFGF21 treatment through its actions on FGF receptor 1(FGFR1) inhibited M1 polarization of microglia and pro-inflammatory cytokine expression by suppressing nuclear factor-kappa B (NF-κB ) and upregulating peroxisome proliferator-activated receptor PPAR-γ. conclusion：In summary, rhFGF21 treatment promoted functional recovery in experimental stroke by modulating microglia/macrophage-mediated neuroinflammation via the NF-κB and PPAR-γ signaling pathways, making it a potential anti-inflammatory agent for stroke treatment. Keywords : rhFGF21, stroke, neuroinflammation, microglia/macrophage, NF-κB, PPAR-γ

Sign in / Sign up

Export Citation Format

Share Document