The NLRP3 inflammasome pathway is activated in sarcoidosis and involved in granuloma formation
| Autor: | Christine Huppertz, Tobias Welte, Franz-Georg Bauernfeind, Benedikt Jäger, Veit Hornung, Peggy Engelhard, Antje Prasse, Amanda Littlewood-Evans, Grazyna Wieczorek, Stephen John Oliver |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Pulmonary and Respiratory Medicine Sarcoidosis Inflammasomes Interleukin-1beta Pilot Projects Mice 03 medical and health sciences 0302 clinical medicine Western blot Downregulation and upregulation NLR Family Pyrin Domain-Containing 3 Protein Animals Humans Medicine Granuloma Innate immune system integumentary system biology medicine.diagnostic_test business.industry Caspase 1 Interleukin Inflammasome 030104 developmental biology Bronchoalveolar lavage 030228 respiratory system Knockout mouse Immunology biology.protein Antibody business medicine.drug |
| Zdroj: | European Respiratory Journal. 55:1900119 |
| ISSN: | 1399-3003 0903-1936 |
| DOI: | 10.1183/13993003.00119-2019 |
| Popis: | Sarcoidosis is a disease characterised by granuloma formation. There is an unmet need for new treatment strategies beyond corticosteroids. The NLRP3 inflammasome pathway is expressed in innate immune cells and senses danger signals to elicit inflammatory interleukin (IL)-1β; it has recently become a druggable target. This prompted us to test the role of the NLRP3 inflammasome and IL-1β pathway in granuloma formation and sarcoidosis.19 sarcoid patients and 19 healthy volunteers were recruited into this pilot study. NLRP3 inflammasome activity was measured in bronchoalveolar lavage (BAL) cells and lung and skin biopsies using immunohistochemistry, Western blot, reverse-transcriptase PCR and ELISA. For in vivo experiments we used the trehalose 6,6′-dimycolate-granuloma mouse model and evaluated lung granuloma burden in miR-223 knockout and NLRP3 knockout mice, as well as the treatment effects of MCC950 and anti-IL-1β antibody therapy.We found strong upregulation of the NLRP3 inflammasome pathway, evidenced by expression of activated NLRP3 inflammasome components, including cleaved caspase-1 and IL-1β in lung granuloma, and increased IL-1β release of BAL cells from sarcoid patients compared to healthy volunteers (p=0.006). mRNA levels of miR-223, a micro-RNA downregulating NLRP3, were decreased and NLRP3 mRNA correspondingly increased in alveolar macrophages from sarcoid patients (pIn conclusion, our data provide evidence of upregulated inflammasome and IL-1β pathway activation in sarcoidosis and suggest both as valid therapeutic targets. |
| Databáze: | OpenAIRE |
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