Dexketoprofen enhances NLRP3 activation via ATPase activity after canonical stimuli.

IF 5.3 2区医学 Q2 IMMUNOLOGY

Inflammopharmacology Pub Date : 2025-09-23 DOI:10.1007/s10787-025-01928-2

Daniel Boy-Ruiz, Juan Miguel Suarez-Rivero, Inés Muela-Zarzuela, Mario D Cordero

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引用次数: 0

Abstract

Inflammasomes are crucial elements of the innate immune system, responsible for triggering inflammation through the activation of caspase-1. Among them, the NLRP3 inflammasome plays a central role in various inflammatory and immune-related disorders. Dexketoprofen (DXK) is a widely used nonsteroidal anti-inflammatory drug (NSAID), although it has not been tested for its effects on the NLRP3 inflammasome pathway. In this study, we explored the influence of DXK on NLRP3 activation and its associated inflammatory responses in human macrophages. Our results showed that even at low concentrations, DXK enhances the release of IL-1β and promotes cell death upon stimulation with LPS and ATP, nigericin and LPS and nigericin, indicating it increases inflammasome activation. Docking and ATPase assays revealed that DXK binds to the NLRP3 NATCH domain, facilitating ATP hydrolysis and NLRP3 activation. Furthermore, treatment with DXK in combination with nigericin further increased IL-1β secretion, while the NLRP3 inhibitor MCC950 reduced the effects of DXK. These findings suggest that DXK amplifies inflammation in macrophages via NLRP3 activation, emphasizing the importance of caution in prolonged use, especially in autoinflammatory diseases where inflammasomes play a significant role.

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右酮洛芬在典型刺激后通过atp酶活性增强NLRP3激活。

炎性小体是先天免疫系统的重要组成部分，负责通过激活caspase-1触发炎症。其中，NLRP3炎症小体在各种炎症和免疫相关疾病中起着核心作用。右酮洛芬（DXK）是一种广泛使用的非甾体抗炎药（NSAID），尽管尚未对其对NLRP3炎症小体途径的影响进行测试。在本研究中，我们探讨了DXK对人巨噬细胞NLRP3激活及其相关炎症反应的影响。我们的研究结果表明，即使在低浓度下，DXK在LPS和ATP、尼日利亚菌素以及LPS和尼日利亚菌素的刺激下，也能增强IL-1β的释放，促进细胞死亡，表明它增加了炎性体的激活。对接和ATP酶分析显示DXK结合NLRP3的NATCH结构域，促进ATP水解和NLRP3活化。此外，DXK与尼日利亚菌素联合治疗进一步增加了IL-1β的分泌，而NLRP3抑制剂MCC950则降低了DXK的作用。这些研究结果表明，DXK通过NLRP3激活放大巨噬细胞的炎症，强调了长期使用的重要性，特别是在炎症小体发挥重要作用的自身炎症性疾病中。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Inflammopharmacology IMMUNOLOGYTOXICOLOGY-TOXICOLOGY

CiteScore

8.00

自引率

3.40%

发文量

200

期刊介绍： Inflammopharmacology is the official publication of the Gastrointestinal Section of the International Union of Basic and Clinical Pharmacology (IUPHAR) and the Hungarian Experimental and Clinical Pharmacology Society (HECPS). Inflammopharmacology publishes papers on all aspects of inflammation and its pharmacological control emphasizing comparisons of (a) different inflammatory states, and (b) the actions, therapeutic efficacy and safety of drugs employed in the treatment of inflammatory conditions. The comparative aspects of the types of inflammatory conditions include gastrointestinal disease (e.g. ulcerative colitis, Crohn''s disease), parasitic diseases, toxicological manifestations of the effects of drugs and environmental agents, arthritic conditions, and inflammatory effects of injury or aging on skeletal muscle. The journal has seven main interest areas: -Drug-Disease Interactions - Conditional Pharmacology - i.e. where the condition (disease or stress state) influences the therapeutic response and side (adverse) effects from anti-inflammatory drugs. Mechanisms of drug-disease and drug disease interactions and the role of different stress states -Rheumatology - particular emphasis on methods of measurement of clinical response effects of new agents, adverse effects from anti-rheumatic drugs -Gastroenterology - with particular emphasis on animal and human models, mechanisms of mucosal inflammation and ulceration and effects of novel and established anti-ulcer, anti-inflammatory agents, or antiparasitic agents -Neuro-Inflammation and Pain - model systems, pharmacology of new analgesic agents and mechanisms of neuro-inflammation and pain -Novel drugs, natural products and nutraceuticals - and their effects on inflammatory processes, especially where there are indications of novel modes action compared with conventional drugs e.g. NSAIDs -Muscle-immune interactions during inflammation [...]