PT - JOURNAL ARTICLE AU - Christine Huppertz AU - Benedikt Jäger AU - Grazyna Wieczorek AU - Peggy Engelhard AU - Stephen J. Oliver AU - Franz-Georg Bauernfeind AU - Amanda Littlewood-Evans AU - Tobias Welte AU - Veit Hornung AU - Antje Prasse TI - The NLRP3 inflammasome pathway is activated in sarcoidosis and involved in granuloma formation AID - 10.1183/13993003.00119-2019 DP - 2020 Jan 01 TA - European Respiratory Journal PG - 1900119 4099 - http://erj.ersjournals.com/content/early/2020/01/03/13993003.00119-2019.short 4100 - http://erj.ersjournals.com/content/early/2020/01/03/13993003.00119-2019.full AB - 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 IL-1β and recently has become a druggable target. This prompted us to test the role of the NLRP3 inflammasome and IL-1β pathway in granuloma formation and sarcoidosis.Nineteen sarcoid patients and 19 healthy volunteers (HV) were recruited into this pilot study. NLRP3 inflammasome activity was measured in BAL-cells and lung and skin biopsies using immunohistochemistry, Western blot, RT-PCR and ELISA. For in vivo experiments we used the trehalose 6,6 dimycolate (TDM)- granuloma mouse model and evaluated lung granuloma burden in miR-223 KO and NLRP3 KO 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 HV (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 (p<0.005). NLRP3 KO mice showed decreased and miR-223 KO mice increased granuloma formation compared to wildtype. Pharmacological interference using NLRP3 pathway inhibitor MCC950 or an anti-IL-1β antibody resulted in reduced granuloma formation (p<0.02).In conclusion, our data provide evidence of upregulated inflammasome and IL-1β pathway activation in sarcoidosis and suggest both as valid therapeutic targets.FootnotesThis manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.Conflict of interest: Dr. Huppertz reports other from Novartis Pharma AG, during the conduct of the study; other from Novartis Pharma AG, outside the submitted work.Conflict of interest: Dr. Jäger has nothing to disclose.Conflict of interest: Dr. Wieczorek reports other from Novartis Pharma AG, during the conduct of the study; other from Novartis Pharma AG, outside the submitted work.Conflict of interest: Dr. Engelhard has nothing to disclose.Conflict of interest: Dr. Oliver reports other from Novartis Pharma AG, during the conduct of the study; other from Novartis Pharma AG, outside the submitted work.Conflict of interest: Dr. Bauernfeind has nothing to disclose.Conflict of interest: Dr. Littlewood-Evans reports other from Novartis Pharma AG, during the conduct of the study; other from Novartis Pharma AG, outside the submitted work.Conflict of interest: Dr. Welte reports grants from Novartis, during the conduct of the study; personal fees from Novartis, outside the submitted work.Conflict of interest: Dr. Hornung has nothing to disclose.Conflict of interest: Dr. Prasse reports grants from Novartis Research Grant, during the conduct of the study; grants and personal fees from Boehringer Ingelheim, personal fees from Roche, personal fees from Novartis, personal fees from Sanofi Aventis, grants and personal fees from Astra Zeneca, outside the submitted work.