The NLRP3 Inflammasome Inhibitor OLT1177® Ameliorates Experimental Allergic Asthma in Mice
| Autor: | Lars P Lunding, Damaris B Skouras, Christina Vock, Charles A Dinarello, Michael Wegmann |
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| Rok vydání: | 2022 |
| Předmět: | |
| Zdroj: | The Journal of Immunology. 208:109.02-109.02 |
| ISSN: | 1550-6606 0022-1767 |
| Popis: | Background The symptoms of asthma arise on the basis of a chronic inflammation of the airways. The NLRP3 inflammasome plays a central role in regulating inflammation e.g. by activating interleukin (IL) 1 cytokines, which in turn promote allergic inflammation. This study aims to evaluate the therapeutic potential of the specific NLRP3 inhibitor OLT1177® on experimental allergic asthma (EAA) in mice. Methods The impact of OLT1177® on NLRP3 expression, caspase-1 activation, and IL-1β release were assessed in vivo and in allergen-restimulated mononuclear cells (MNC) from ovalbumin (OVA)-sensitized mice. The effect of intra-peritoneal OLT1177®-treatment on OVA- and house dust mite (HDM) EAA and on poly(I:C)-triggered exacerbation of EAA were assessed. Furthermore, the effect of oropharyngeal aspiration of OLT1177® and oral OLT1177® via an enriched diet were also evaluated in mice with OVA-induced EAA. Results OLT1177® reduced NLRP3 expression, caspase-1 activation, and levels of activated IL-1β in vitro and in mice with OVA-induced EAA. Intra-peritoneal treatment with OLT1177® significantly diminished allergic airway inflammation, mucus hyperproduction, and airway hyperresponsiveness (AHR) in mice with OVA- and HDM-induced EAA as well as in mice with poly(I:C)-triggered exacerbation of EAA. While oropharyngeal aspiration of OLT1177® had no effect on EAA, oral OLT1177® via feeding an enriched diet markedly reduced all pathophysiologic hallmarks of EAA in mice. Conclusion Intra-peritoneal and oral delivery of OLT1177® is effective to inhibit the NLRP3 inflammasome in vivo and to treat EAA in mice. This study was mainly supported by the German Center for Lung Research (DZL). The study was also supported by Olatec Therapeutics LLC and the Interleukin Foundation. |
| Databáze: | OpenAIRE |
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