Huppertz, Christine, Wieczorek, Grazyna, Littlewood-Evans, Amanda, Oliver, Stephen, Jaeger, Benedikt, Engelhard, Peggy, Bauernfeind, Franz-Georg, Welte, Tobias, Hornung, Veit and Prasse, Antje (2020) The NLRP3 inflammasome pathway is activated in sarcoidosis and involved in granuloma formation. The European respiratory journal. ISSN 13993003

Abstract

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.

Item Type:	Article
Date Deposited:	10 Mar 2020 00:45
Last Modified:	10 Mar 2020 00:45
URI:	https://oak.novartis.com/id/eprint/41899