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Fluorofenidone inhibits macrophage IL-1β production by suppressing inflammasome activity
Miaomiao Lu1, Wenjun Yang2, Zhangzhe Peng2
1Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; Department of Nephrology, The First Affiliated of Liaoning Medical University, Jinzhou, Liaoning 121001, China.
Abstract:
Interleukin-1 beta (IL-1β) is a potent pro-inflammatory and pro-fibrotic cytokine that plays an important role in renal fibrosis. Fluorofenidone (AKF-PD) is a novel pyridone agent that exerts a strong renal anti-fibrotic effect. We previously found that administration of AKF-PD could significantly attenuate IL-1β production in vitro and in vivo. However, the underlying mechanism is not fully understood. Here we show that AKF-PD has no effect on the expression of pro-IL-1β in activated mouse macrophages in vitro. Instead, AKF-PD inhibits the inflammasome, lowering caspase-1 levels and thereby decreasing cleavage of pro-IL-1β into IL-1β. AKF-PD was found to block inflammasome activity induced by various signals, including ATP, alum crystals, and Salmonella typhimurium. These results provide a novel mechanistic insight into how AKF-PD exerts its anti-inflammatory and anti-fibrotic activities, and suggest that AKF-PD might block IL-1β production via suppression of inflammasomes in renal fibrosis. In addition, the results suggest that AKF-PD may be of therapeutic potential in other inflammasome-related diseases.
Insights
Fluorofenidone (AKF-PD) reduces kidney fibrosis by inhibiting the inflammasome, a key pathway for interleukin-1 beta (IL-1β) production. This novel mechanism offers therapeutic potential for inflammasome-related diseases.
Area of Science:
- Immunology
- Nephrology
- Pharmacology
Background:
- Interleukin-1 beta (IL-1β) is a critical cytokine in renal fibrosis.
- Fluorofenidone (AKF-PD) demonstrates renal anti-fibrotic effects.
- Previous studies indicated AKF-PD attenuates IL-1β production, but the mechanism was unclear.
Purpose of the Study:
- To elucidate the mechanism by which AKF-PD reduces IL-1β production.
- To investigate AKF-PD's effect on inflammasome activation in macrophages.
- To explore AKF-PD's therapeutic potential in inflammasome-mediated diseases.
Main Methods:
- Assessed AKF-PD's effect on pro-IL-1β expression in activated mouse macrophages.
- Investigated AKF-PD's impact on inflammasome components, including caspase-1.
- Evaluated AKF-PD's ability to inhibit inflammasome activation induced by ATP, alum crystals, and Salmonella typhimurium.
Main Results:
- AKF-PD did not affect pro-IL-1β expression in macrophages.
- AKF-PD inhibited inflammasome activation by reducing caspase-1 levels.
- This reduction led to decreased cleavage of pro-IL-1β into mature IL-1β.
- AKF-PD blocked inflammasome activity triggered by diverse stimuli.
Conclusions:
- AKF-PD exerts anti-inflammatory and anti-fibrotic effects by suppressing inflammasome activity.
- AKF-PD inhibits IL-1β production via inflammasome suppression, offering a novel therapeutic mechanism for renal fibrosis.
- AKF-PD shows promise for treating other inflammasome-related conditions.
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