Ginsenosides enhance P2X7-dependent cytokine secretion from LPS-primed rodent macrophages

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Abstract

The activation of P2X7 is a well-known stimulus for the NLRP3-caspase 1 inflammasome and subsequent rapid IL-1β secretion from monocytes and macrophages. Here we show that positive allosteric modulators of P2X7, ginsenosides, can enhance the release of three important cytokines, IL-1β, IL-6 and TNF-α from LPS-primed rodent macrophages using the J774 mouse macrophage cell line and primary rat peritoneal macrophages. We compared the immediate P2X7 responses in un-primed and LPS-primed macrophages and found no difference in calcium response amplitude or kinetics. These results suggest that under inflammatory conditions positive allosteric modulators are capable of increasing cytokine secretion at lower concentrations of ATP, thus boosting the initial pro-inflammatory signal. This may be important in the control of intracellular infections.

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Cytokines and chemokines: At the crossroads of cell signalling and inflammatory disease.

Mark D Turner, Belinda Nedjai, Tara Hurst … (2014)

Inflammation occurs as a result of exposure of tissues and organs to harmful stimuli such as microbial pathogens, irritants, or toxic cellular components. The primary physical manifestations of inflammation are redness, swelling, heat, pain, and loss of function to the affected area. These processes involve the major cells of the immune system, including monocytes, macrophages, neutrophils, basophils, dendritic cells, mast cells, T-cells, and B-cells. However, examination of a range of inflammatory lesions demonstrates the presence of specific leukocytes in any given lesion. That is, the inflammatory process is regulated in such a way as to ensure that the appropriate leukocytes are recruited. These events are in turn controlled by a host of extracellular molecular regulators, including members of the cytokine and chemokine families that mediate both immune cell recruitment and complex intracellular signalling control mechanisms that characterise inflammation. This review will focus on the role of the main cytokines, chemokines, and their receptors in the pathophysiology of auto-inflammatory disorders, pro-inflammatory disorders, and neurological disorders involving inflammation.

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The P2X7 Receptor in Infection and Inflammation.

Francesco Di Virgilio, Alba Clara Sarti, Anna Giuliani … (2017)

Adenosine triphosphate (ATP) accumulates at sites of tissue injury and inflammation. Effects of extracellular ATP are mediated by plasma membrane receptors named P2 receptors (P2Rs). The P2R most involved in inflammation and immunity is the P2X7 receptor (P2X7R), expressed by virtually all cells of innate and adaptive immunity. P2X7R mediates NLRP3 inflammasome activation, cytokine and chemokine release, T lymphocyte survival and differentiation, transcription factor activation, and cell death. Ten human P2RX7 gene splice variants and several SNPs that produce complex haplotypes are known. The P2X7R is a potent stimulant of inflammation and immunity and a promoter of cancer cell growth. This makes P2X7R an appealing target for anti-inflammatory and anti-cancer therapy. However, an in-depth knowledge of its structure and of the associated signal transduction mechanisms is needed for an effective therapeutic development.

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The P2X7 Receptor in Inflammatory Diseases: Angel or Demon?

Luiz E. B. Savio, Paola de Andrade Mello, Cleide Gonçalves da Silva … (2018)

Under physiological conditions, adenosine triphosphate (ATP) is present at low levels in the extracellular milieu, being massively released by stressed or dying cells. Once outside the cells, ATP and related nucleotides/nucleoside generated by ectonucleotidases mediate a high evolutionary conserved signaling system: the purinergic signaling, which is involved in a variety of pathological conditions, including inflammatory diseases. Extracellular ATP has been considered an endogenous adjuvant that can initiate inflammation by acting as a danger signal through the activation of purinergic type 2 receptors—P2 receptors (P2Y G-protein coupled receptors and P2X ligand-gated ion channels). Among the P2 receptors, the P2X7 receptor is the most extensively studied from an immunological perspective, being involved in both innate and adaptive immune responses. P2X7 receptor activation induces large-scale ATP release via its intrinsic ability to form a membrane pore or in association with pannexin hemichannels, boosting purinergic signaling. ATP acting via P2X7 receptor is the second signal to the inflammasome activation, inducing both maturation and release of pro-inflammatory cytokines, such as IL-1β and IL-18, and the production of reactive nitrogen and oxygen species. Furthermore, the P2X7 receptor is involved in caspases activation, as well as in apoptosis induction. During adaptive immune response, P2X7 receptor modulates the balance between the generation of T helper type 17 (Th17) and T regulatory (Treg) lymphocytes. Therefore, this receptor is involved in several inflammatory pathological conditions. In infectious diseases and cancer, P2X7 receptor can have different and contrasting effects, being an angel or a demon depending on its level of activation, cell studied, type of pathogen, and severity of infection. In neuroinflammatory and neurodegenerative diseases, P2X7 upregulation and function appears to contribute to disease progression. In this review, we deeply discuss P2X7 receptor dual function and its pharmacological modulation in the context of different pathologies, and we also highlight the P2X7 receptor as a potential target to treat inflammatory related diseases.

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Contributors

Kshitija Dhuna:

Bio :

Kshitija Dhuna

Kshitija completed her PhD at RMIT University (Melbourne) from 2014-2019 working on P2X7 receptors and the development of novel pharmacological tools under the supervision of Dr Leanne Stokes (now at University of East Anglia, UK). She has contributed to several peer-reviewed articles and presented her work at many national and international conferences. Leveraging her biomedical research and tertiary teaching experience, Kshitija is presently working as a senior secondary Chemistry and Biology teacher to inspire and engage more students in STEM-based career pathways.

Leanne Stokes:

ORCID: http://orcid.org/0000-0003-4013-6781

l.stokes@uea.ac.uk

Journal

Journal ID (nlm-ta): Purinergic Signal

Journal ID (iso-abbrev): Purinergic Signal

Title: Purinergic Signalling

Publisher: Springer Netherlands (Dordrecht )

ISSN (Print): 1573-9538

ISSN (Electronic): 1573-9546

Publication date (Electronic): 14 April 2023

Publication date PMC-release: 14 April 2023

Publication date (Print): February 2024

Volume: 20

Issue: 1

Pages: 65-71

Affiliations

[1 ]School of Health & Biomedical Sciences, RMIT University, ( https://ror.org/04ttjf776) Bundoora, VIC 2038 Australia

[2 ]School of Pharmacy, University of East Anglia, ( https://ror.org/026k5mg93) Norwich Research Park, Norwich, NR4 7TJ UK

Author information

Leanne Stokes http://orcid.org/0000-0003-4013-6781

Article

Publisher ID: 9935

DOI: 10.1007/s11302-023-09935-0

PMC ID: 10828361

PubMed ID: 37055674

SO-VID: c53bb5ca-8270-4c5d-8144-ce1a33f4fb15

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 31 January 2023

Date accepted : 13 March 2023

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100001780, RMIT University;

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ScienceOpen disciplines: Cell biology

Keywords: ginsenoside,cytokine,macrophage,p2x7,atp

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ScienceOpen disciplines: Cell biology

Keywords: ginsenoside, cytokine, macrophage, p2x7, atp

Ginsenosides enhance P2X7-dependent cytokine secretion from LPS-primed rodent macrophages

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GLUT4 biology

Most cited references 17

Cytokines and chemokines: At the crossroads of cell signalling and inflammatory disease.

The P2X7 Receptor in Infection and Inflammation.

The P2X7 Receptor in Inflammatory Diseases: Angel or Demon?

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