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Updated: Aug 15, 2025
Author Spotlight: THP-1 Macrophage Response to LPS/ATP — Unveiling the Pyroptosis, Apoptosis, and Necroptosis Spectrum
Published on: May 3, 2024
Targeting Noncanonical Pyroptosis With a Small Molecular Inhibitor Alleviates Inflammation in the LPS-Induced
Yun Zhang1,2,3, Nenghua Zhou4, Yan Jiao5
1Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, China.
Purpose:
Pyroptosis, a novel proinflammatory programmed cell death, has been implicated in some ocular diseases. Of special note is the noncanonical pyroptosis that has recently been recognized to play a critical role in microbial keratitis. We previously discovered a new potent small molecular pyroptosis inhibitor, J114. In this investigation, we will explore whether J114 is able to inhibit the noncanonical pyroptosis and the underlying mechanism. Then a lipopolysaccharide (LPS)-induced keratitis mouse model will be used to evaluate the therapeutic effect of J114 in vivo.
Methods:
In vitro, macrophages originating from humans or mice were stimulated with intracellular LPS to induce noncanonical pyroptosis activation. in vivo, acute keratitis in mouse was induced by LPS intrastromal injection. We verified the protective effect of J114 on noncanonical pyroptosis. Clinical scoring, histological observation, macrophage localization, and quantification of pyroptotic markers in the cornea were used to characterize the therapeutic effects.
Results:
J114 substantially inhibited the noncanonical pyroptosis and the release of inflammatory cytokines by suppressing the activation of caspase-4/5/11 and the noncanonical NLRP3 inflammasome through blocking the NLRP3-ASC interaction. in vivo, J114 protected against LPS-induced noncanonical pyroptosis of acute keratitis, as manifested by alleviated clinical manifestations and histological disorders, and relieved inflammatory reactions.
Conclusions:
In this study, we found that J114 could efficiently inhibit LPS-induced noncanonical pyroptosis and revealed the underlying mechanism. This compound displayed significant anti-inflammatory activity in the LPS-induced keratitis mouse model. All the findings indicated that J114 could be a potential lead compound for drug development against inflammatory ocular surface diseases.
Insights
The small molecule J114 effectively inhibits noncanonical pyroptosis, a key driver of microbial keratitis. This compound shows therapeutic potential for treating inflammatory eye diseases by reducing inflammation and protecting the cornea.
Area of Science:
- Ophthalmology
- Immunology
- Pharmacology
Background:
- Pyroptosis, a pro-inflammatory programmed cell death, is implicated in ocular diseases.
- Noncanonical pyroptosis plays a critical role in microbial keratitis.
- A novel small molecule pyroptosis inhibitor, J114, was previously discovered.
Purpose of the Study:
- To investigate J114's ability to inhibit noncanonical pyroptosis.
- To elucidate the underlying mechanism of J114's action.
- To evaluate J114's therapeutic effect in a lipopolysaccharide (LPS)-induced keratitis mouse model.
Main Methods:
- In vitro: Macrophages stimulated with intracellular LPS to induce noncanonical pyroptosis.
- In vivo: Acute keratitis induced by LPS intrastromal injection in mice.
- Assessment of J114's protective effect using clinical scoring, histology, and pyroptotic marker quantification.
Main Results:
- J114 inhibited noncanonical pyroptosis by suppressing caspase-4/5/11 activation and NLRP3 inflammasome assembly.
- J114 blocked the NLRP3-ASC interaction, reducing inflammatory cytokine release.
- In vivo, J114 alleviated clinical and histological signs of LPS-induced keratitis, reducing inflammation.
Conclusions:
- J114 efficiently inhibits LPS-induced noncanonical pyroptosis through a defined mechanism.
- J114 demonstrates significant anti-inflammatory activity in a keratitis mouse model.
- J114 is a potential lead compound for developing drugs against inflammatory ocular surface diseases.
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