Electrostimulation of the carotid sinus nerve in mice attenuates inflammation via glucocorticoid receptor on myeloid immune cells

Abstract Background The carotid bodies and baroreceptors are sensors capable of detecting various physiological parameters that signal to the brain via the afferent carotid sinus nerve for physiological adjustment by efferent pathways. Because receptors for inflammatory mediators are expressed by these sensors, we and others have hypothesised they could detect changes in pro-inflammatory cytokine blood levels and eventually trigger an anti-inflammatory reflex. Methods To test this hypothesis, we surgically isolated the carotid sinus nerve and implanted an electrode, which could deliver an electrical stimulation package prior and following a lipopolysaccharide injection. Subsequently, 90 min later, blood was extracted, and cytokine levels were analysed. Results Here, we found that carotid sinus nerve electrical stimulation inhibited lipopolysaccharide-induced tumour necrosis factor production in both anaesthetised and non-anaesthetised conscious mice. The anti-inflammatory effect of carotid sinus nerve electrical stimulation was so potent that it protected conscious mice from endotoxaemic shock-induced death. In contrast to the mechanisms underlying the well-described vagal anti-inflammatory reflex, this phenomenon does not depend on signalling through the autonomic nervous system. Rather, the inhibition of lipopolysaccharide-induced tumour necrosis factor production by carotid sinus nerve electrical stimulation is abolished by surgical removal of the adrenal glands, by treatment with the glucocorticoid receptor antagonist mifepristone or by genetic inactivation of the glucocorticoid gene in myeloid cells. Further, carotid sinus nerve electrical stimulation increases the spontaneous discharge activity of the hypothalamic paraventricular nucleus leading to enhanced production of corticosterone. Conclusion Carotid sinus nerve electrostimulation attenuates inflammation and protects against lipopolysaccharide-induced endotoxaemic shock via increased corticosterone acting on the glucocorticoid receptor of myeloid immune cells. These results provide a rationale for the use of carotid sinus nerve electrostimulation as a therapeutic approach for immune-mediated inflammatory diseases.

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Molecular Docking Study for Analyzing the Inhibitory Effect of Anti-inflammatory Plant Compound Against Tumour Necrosis Factor (TNF-α)

Current Drug Therapy ◽

10.2174/1574885513666180503145352 ◽

2019 ◽

Vol 14 (1) ◽

pp. 85-90

Author(s):

Sagarika Biswas

Keyword(s):

Molecular Docking ◽

Tumour Necrosis Factor ◽

Tumour Necrosis ◽

Docking Study ◽

Developed Countries ◽

Inhibitory Effect ◽

Molecular Docking Study ◽

Drug Designing ◽

Anti Inflammatory ◽

Necrosis Factor

Background: Rheumatoid Arthritis (RA) is an autoimmune disorder of symmetric synovial joints which is characterized by the chronic inflammation with 0.5-1% prevalence in developed countries. Presence of persistent inflammation is attributed to the major contribution of key inflammatory cytokine and tumour necrosis factor- alpha (TNF- α). Recent drug designing studies are developing TNF-α blockers to provide relief from the symptoms of the disease such as pain and inflammation. Available blockers are showing certain limitations such as it may enhance the rate of tuberculosis (TB) occurrence, lymphoma risk, cost issues and certain infections are major concern. Discussed limitations implicated a need of development of some alternative drugs which exhibit fewer side effects with low cost. Therefore, we have identified anti-inflammatory compounds in an underutilized fruit of Baccaurea sapida (B.sapida) in our previous studies. Among them quercetin have been identified as the most potent lead compound for drug designing studies of RA. Methods: In the present article, characterization of quercetin has been carried out to check its drug likeliness and molecular docking study has been carried out between TNF- α and quercetin by using AutoDock 4.2.1 software. Further, inhibitory effect of B. sapida fruit extract on RA plasma has been analysed through immunological assay ELISA. Results: Our in-silico analysis indicated that quercetin showed non carcinogenic reaction in animal model and it may also cross the membrane barrier easily. We have studied the ten different binding poses and best binding pose of TNF-α and quercetin showed -6.3 kcal/mol minimum binding energy and 23.94 µM inhibitory constant. In addition to this, ELISA indicated 2.2 down regulated expression of TNF-α in RA compared to control. Conclusion: This study may further be utilized for the drug designing studies to reduce TNF-α mediated inflammation in near future. This attempt may also enhance the utilization of this plant worldwide.

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Disseminated Mycobacterium avium infection in a child with decreased tumour necrosis factor production

European Journal of Pediatrics ◽

10.1007/s004310050583 ◽

1997 ◽

Vol 156 (3) ◽

pp. 204-206 ◽

Cited By ~ 6

Author(s):

D. Tuerlinckx ◽

C. Vermylen ◽

B. Brichard ◽

J. Ninane ◽

G. Cornu

Keyword(s):

Tumour Necrosis Factor ◽

Mycobacterium Avium ◽

Tumour Necrosis ◽

Factor Production ◽

Tumour Necrosis Factor Production ◽

Avium Infection ◽

Mycobacterium Avium Infection ◽

Necrosis Factor

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Suppression of tumour necrosis factor production from mononuclear cells by a novel synthetic compound, CLX-090717

Rheumatology ◽

10.1093/rheumatology/ken398 ◽

2008 ◽

Vol 48 (1) ◽

pp. 32-38 ◽

Cited By ~ 10

Author(s):

P. F. Sumariwalla ◽

C. D. Palmer ◽

L. B. Pickford ◽

M. Feldmann ◽

B. M. J. Foxwell ◽

...

Keyword(s):

Tumour Necrosis Factor ◽

Tumour Necrosis ◽

Mononuclear Cells ◽

Synthetic Compound ◽

Factor Production ◽

Tumour Necrosis Factor Production ◽

Necrosis Factor

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Effects of esculentoside A on turnour necrosis factor production by mice peritoneal macrophages

Mediators of Inflammation ◽

10.1155/s0962935192000565 ◽

1992 ◽

Vol 1 (6) ◽

pp. 375-377 ◽

Cited By ~ 5

Author(s):

Fang Jun ◽

Zheng Qin Yue ◽

Wang Hong Bin ◽

Ju Dian Wen ◽

Yi Yang Hua

Keyword(s):

Tumour Necrosis Factor ◽

Tumour Necrosis ◽

Inflammatory Mediator ◽

Platelet Activating Factor ◽

Peritoneal Macrophages ◽

Dependent Manner ◽

Anti Inflammatory ◽

Dose Dependent ◽

Necrosis Factor ◽

Inflammatory Effect

Esculentoside A (EsA) is a saponin isolated from the roots of Phytolacca esculenta. Previous experiments showed that it had strong anti-inflammatory effects. Tumour necrosis factor (TNF) is an important inflammatory mediator. In order to study the mechanism of the anti-inflammatory effect of EsA, it was determined whether TNF production from macrophages was altered by EsA under lipopolysaccharide (LPS) stimulated conditions. EsA was found to decrease both extracellular and cell associated TNF production in a dose dependent manner at concentrations higher than 1 μmol/l EsA. Previous studies have showed that EsA reduced the releasing of platelet activating factor (PAF) from rat macrophages. The reducing effects of EsA on the release of TNF and PAF may explain its anti-inflammatory effect.

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Complex Modulation of Cytokine Induction by Endotoxin and Tumour Necrosis Factor from Peritoneal Macrophages of Rats by Diets Containing Fats of Different Saturated, Monounsaturated and Polyunsaturated Fatty Acid Composition

Clinical Science ◽

10.1042/cs0870173 ◽

1994 ◽

Vol 87 (2) ◽

pp. 173-178 ◽

Cited By ~ 31

Author(s):

P. S. Tappia ◽

R. F. Grimble

Keyword(s):

Fatty Acids ◽

Polyunsaturated Fatty Acids ◽

Olive Oil ◽

Tumour Necrosis Factor ◽

Tumour Necrosis ◽

Corn Oil ◽

Interleukin 1 ◽

Coconut Oil ◽

Tumour Necrosis Factor Production ◽

Necrosis Factor

1. Responses to cytokines and other inflammatory stimuli have been shown to be enhanced by fats rich in n − 6 polyunsaturated fatty acids and suppressed by fats rich in n − 3 polyunsaturated fatty acids and oleic acid or poor in n − 6 polyunsaturated fatty acids. 2. Corn oil is rich and coconut oil, olive oil and butter are poor in n − 6 polyunsaturated fatty acids. Olive oil and butter are rich in oleic acid. Fish oil is rich in n − 3 polyunsaturated fatty acids. 3. The present study examines the effects of feeding standard chow or corn, coconut, fish and olive oils and butter for 4 and 8 weeks on subsequent cytokine production by peritoneal macrophages of rats. 4. Tumour necrosis factor production in response to a lipopolysaccharide stimulus and interleukin-1 and interleukin-6 production in response to a tumour necrosis factor challenge were studied. 5. All fats produced a small, but statistically insignificant, reduction in tumour necrosis factor production, which was greatest for olive oil at 8 weeks. 6. After 4 weeks, fish and olive oil significantly reduced interleukin-1 production. After 8 weeks, coconut oil suppressed production of the cytokine, and the inhibitory effect of fish oil was still apparent. After 8 weeks, corn and olive oil enhanced interleukin-1 production. 7. After 4 weeks of feeding, fish and olive oil enhanced interleukin-6 production. After 8 weeks, the enhancement by these fats increased, and corn oil and butter also enhanced production. Coconut oil produced no modulatory effect. 8. Only in the cases of the effect of fish and coconut oil in interleukin-1 production, corn oil on interleukin-1 and interleukin-6 production and olive oil in tumour necrosis factor production, were the effects of fats on cytokine production in concordance with their modulatory effects on responses to cytokines and other inflammatory agents in vivo.

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