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The Angiotensin II Receptor Neprilysin Inhibitor LCZ696 Inhibits the NLRP3 Inflammasome By Reducing Mitochondrial Dysfunction in Macrophages and Alleviates Dextran Sulfate Sodium-induced Colitis in a Mouse Model

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Abstract

The intracellular sensor protein complex known as the NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasome plays a crucial role in regulating inflammatory diseases by overseeing the production of interleukin (IL)-1β and IL-18. Targeting its abnormal activation with drugs holds significant promise for inflammation treatment. This study highlights LCZ696, an angiotensin receptor-neprilysin inhibitor, as an effective suppressor of NLRP3 inflammasome activation in macrophages stimulated by ATP, nigericin, and monosodium urate. LCZ696 also reduces caspase-11 and GSDMD activation, lactate dehydrogenase release, propidium iodide uptake, and the extracellular release of NLRP3 and apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) in ATP-activated macrophages, suggesting a potential mitigation of pyroptosis. Mechanistically, LCZ696 lowers mitochondrial reactive oxygen species and preserves mitochondrial integrity. Importantly, it does not significantly impact NLRP3, proIL-1β, inducible nitric oxide synthase, cyclooxygenase-2 expression, or NF-κB activation in lipopolysaccharide-activated macrophages. LCZ696 partially inhibits the NLRP3 inflammasome through the induction of autophagy. In an in vivo context, LCZ696 alleviates NLRP3-associated colitis in a mouse model by reducing colonic expression of IL-1β and tumor necrosis factor-α. Collectively, these findings suggest that LCZ696 holds significant promise as a therapeutic agent for ameliorating NLRP3 inflammasome activation in various inflammatory diseases, extending beyond its established use in hypertension and heart failure treatment.

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Data Availability

The data used to support the findings of this study are available from the corresponding author upon request.

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Funding

This research work is supported by the funding from the National Science and Technology Council, Taiwan (MOST 111-2628-B-197-001-MY3 and NSTC 112-2313-B-197-002 to K.-F. H.; MOST 111-2811-B-197-001 and NSTC 112-2811-B-197-002 to H.-W. C.), Tri-Service General Hospital, Taipei, Taiwan (TSGH-D-111048 to C.-H. W.; TSGH-C01-110015 to S.-M. C.; TSGH-C01-110016 to C.-C. C.) and Teh-Tzer Study Group for Human Medical Research Foundation (B1101034 to K.-F. H.).

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  1. Hsiao-Wen Chiu and Chun-Hsien Wu contributed equally to this work.

Authors and Affiliations

  1. Department of Biotechnology and Animal Science, National Ilan University, Ilan, Taiwan

    Hsiao-Wen Chiu, Wen-Yu Lin, Wei-Ting Wong & Kuo-Feng Hua

  2. Division of Cardiology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan

    Chun-Hsien Wu, Wen-Yu Lin, Wei-Che Tsai, Shu-Meng Cheng, Cheng-Chung Cheng & Shih-Ping Yang

  3. Division of Neurosurgery, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan

    Hsien-Ta Hsu

  4. School of Medicine, Buddhist Tzu Chi University, Hualien, Taiwan

    Hsien-Ta Hsu

  5. Division of Wood Cellulose, Taiwan Forestry Research Institute, Taipei, Taiwan

    Chen-Lung Ho

  6. Department of Laboratory Medicine, Linsen, Chinese Medicine and Kunming Branch, Taipei City Hospital, Taipei, Taiwan

    Lan-Hui Li

  7. Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan

    Kuo-Feng Hua

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  1. Hsiao-Wen Chiu
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Contributions

L.-H. L. and K.-F. H. is the guarantor of the article. L.-H. L. and K.-F. H. conceived and designed the study. H.-W. C., C.-H. W., W.-Y. L., W.-T. W. and W.-C. T. performed the experiments and analyzed the data. C.-L. H. assisted with some experiments. H.-T. H., S.-M. C., C.-C. C. and S.-P. Y. contributed to critical revision of the manuscript. H.-W. C., C.-H. W., L.-H. L. and K.-F. H. wrote and finished the manuscript. All authors participated in revising the manuscript and approved the final version.

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Correspondence to Lan-Hui Li or Kuo-Feng Hua.

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Chiu, HW., Wu, CH., Lin, WY. et al. The Angiotensin II Receptor Neprilysin Inhibitor LCZ696 Inhibits the NLRP3 Inflammasome By Reducing Mitochondrial Dysfunction in Macrophages and Alleviates Dextran Sulfate Sodium-induced Colitis in a Mouse Model. Inflammation (2024). https://doi.org/10.1007/s10753-023-01939-7

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