ATP/P2X7 receptor signaling as a potential anti-inflammatory target of natural polyphenols

Area of Science:

• Immunology
• Pharmacology
• Natural Product Chemistry

Background:

• Innate immune cells, like macrophages, activate inflammatory responses upon detecting pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs).
• Adenosine 5 -triphosphate (ATP) acts as a DAMP, exacerbating lipopolysaccharide (LPS)-induced inflammation, particularly through the P2X7 receptor (P2X7R).

Purpose of the Study:

• To investigate ATP/P2X7R signaling as a target for natural polyphenols to mitigate LPS-stimulated inflammation.
• To identify specific polyphenols capable of inhibiting ATP/P2X7R-mediated inflammatory responses.

Main Methods:

• Utilized siRNA-mediated knockdown and specific antagonists to confirm P2X7R involvement in ATP-enhanced inflammation in LPS-stimulated J774.1 mouse macrophages.
• Screened 42 natural polyphenols for their ability to inhibit ATP/P2X7R-induced calcium influx.
• Assessed the anti-inflammatory effects of promising polyphenol candidates, including interleukin-1β secretion.

Main Results:

• Confirmed that ATP-induced inflammatory responses in LPS-stimulated macrophages are mediated by P2X7R.
• Identified several polyphenols with significant inhibitory effects on ATP/P2X7R-induced calcium influx.
• Baicalein, a flavonoid, demonstrated potent inhibition of ATP-induced inflammation and interleukin-1β secretion by blocking ATP/P2X7R signaling.

Conclusions:

• ATP/P2X7R signaling is a key contributor to excessive inflammatory responses.
• Natural polyphenols, particularly baicalein, represent a promising therapeutic strategy for targeting ATP/P2X7R-mediated inflammation.
• This study highlights a novel anti-inflammatory mechanism for natural compounds targeting purinergic signaling pathways.