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Inhibition of NLRP3 Inflammasome Prevents LPS-Induced Inflammatory Hyperalgesia in Mice: Contribution of NF-κB, Caspase-1/11, ASC, NOX, and NOS Isoforms

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Abstract

The nucleotide-binding domain and leucine-rich repeat protein 3 (NLRP3), an intracellular signaling molecule that senses many environmental- and pathogen/host-derived factors, has been implicated in the pathogenesis of several diseases associated with inflammation. It has been suggested that NLRP3 inflammasome inhibitors may have a therapeutic potential in the treatment of NLRP3-related inflammatory diseases. The aim of this study was to determine whether inhibition of NLRP3 inflammasome prevents inflammatory hyperalgesia induced by lipopolysaccharide (LPS) in mice as well as changes in expression/activity of nuclear factor κB (NF-κB), caspase-1/11, nicotinamide adenine dinucleotide phosphate oxidase (NOX), and endothelial/neuronal/inducible nitric oxide synthase (eNOS/nNOS/iNOS) that may regulate NLRP3/apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC)/pro-caspase-1 inflammasome formation and activity by using a selective NLRP3 inflammasome inhibitor, MCC950. Male mice received saline (10 ml/kg; i.p.), LPS (10 mg/kg; i.p.), and/or MCC950 (3 mg/kg; i.p.). Reaction time to thermal stimuli within 1 min was evaluated after 6 h. The mice were killed and the brains, hearts, and lungs were collected for measurement of NF-κB, caspase-1, caspase-11, NLRP3, ASC, NOX subunits (gp91phox; NOX2), and p47phox; NOXO2), nitrotyrosine, eNOS, nNOS, iNOS, and β-actin protein expression, NOS activity, and interleukin (IL)-1β levels. LPS-induced hyperalgesia was associated with a decrease in eNOS, nNOS, and iNOS protein expression and activity as well as an increase in expression of NF-κB p65, caspase-1 p20, caspase-11 p20, NLRP3, ASC, gp91phox, p47phox, and nitrotyrosine proteins in addition to elevated IL-1β levels. The LPS-induced changes were prevented by MCC950. The results suggest that inhibition of NLRP3/ASC/pro-caspase-1 inflammasome formation and activity prevents inflammatory hyperalgesia induced by LPS in mice as well as changes in NF-κB, caspase-11, NOX2, NOXO2, and eNOS/nNOS/iNOS expression/activity.

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Authors and Affiliations

  1. Department of Pharmacology, Faculty of Pharmacy, Mersin University, Yenisehir Campus, Mersin, 33169, Turkey

    Abdurrahman Dolunay, Sefika Pinar Senol, Meryem Temiz-Resitoglu, Demet Sinem Guden, Ayse Nihal Sari, Seyhan Sahan-Firat & Bahar Tunctan

Authors
  1. Abdurrahman Dolunay
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  2. Sefika Pinar Senol
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  3. Meryem Temiz-Resitoglu
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  4. Demet Sinem Guden
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  5. Ayse Nihal Sari
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  6. Seyhan Sahan-Firat
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  7. Bahar Tunctan
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Corresponding author

Correspondence to Bahar Tunctan.

Ethics declarations

All experiments were carried out according to the National Institutes of Health Guide for the Care and Use of Laboratory Animals, and the study protocol was approved by the Ethics Committee of Mersin University School of Medicine.

Conflict of Interest

The authors declare that they have no conflict of interest.

Funding

Financial support was provided by grants from the TUBITAK (SBAG-S215047) and the Mersin University (BAP-2016-1-TP2-1427). The results of this study were included in the Master’s Thesis of Pharm. M.S. Abdurrahman Dolunay.

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Dolunay, A., Senol, S.P., Temiz-Resitoglu, M. et al. Inhibition of NLRP3 Inflammasome Prevents LPS-Induced Inflammatory Hyperalgesia in Mice: Contribution of NF-κB, Caspase-1/11, ASC, NOX, and NOS Isoforms. Inflammation 40, 366–386 (2017). https://doi.org/10.1007/s10753-016-0483-3

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  • DOI: https://doi.org/10.1007/s10753-016-0483-3

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