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The NLRP3 inflammasome and IL-1β pathway have a pivotal role in granuloma formation of sarcoidosis

 
: Prasse, Antje; Engelhard, P.; Plappert, Linda; Hornung, V.; Bauernfeind, F.; Jäger, Benedikt

American Journal of Respiratory and Critical Care Medicine 197 (2018), Abstract A4492
ISSN: 1073-449X
ISSN: 0003-0805
ISSN: 1535-4970
American Thoracic Society (ATS International Conference) <2018, San Diego/Calif.>
Englisch
Abstract
Fraunhofer ITEM ()

Abstract
Introduction: Sarcoidosis is an inflammatory lung disease characterized by granuloma formation. The NLRP3 inflammasome is crucially inolved in the production of biologically active IL-1β and IL-18. Objectives: We investigated the role of the NLRP3 inflammasome in granuloma formation in sarcoidosis and the effect of potential treatment strategies inhibiting the activation of this pathway. Methods: We analyzed BAL cells of 36 patients with sarcoidosis and 37 healthy volunteers (HV). NLRP3 inflammasome activity of AM was measured either by caspase-1p20 expression using Western Blot or IL-1β production (ELISA). Relative NLRP3/GAPDH and miRNA-223/U6 expression was detected by RT-PCR. NLRP3 inflammasome activation was induced by priming w LPS (1µg/ml) and subsequent activation with either ATP (1nM) or Nigericin (NIG 10µM) for 6h. We used the TDM-granuloma mouse model to evaluate lung granuloma burden in miR-223 KO and NLRP3 KO mice as well as to test the effects of the NLRP3 pathway inhibitor MCC950. Results: We found a significant increase in both spontaneous and LPS+NIGstimulated IL-1β production of AM derived from sarcoid patients compared to control AM ( p=0.01, p<0.0005 respectively). After specific stimulation with LPS + NIG we also detected an increase in caspase-1p20 expression of AM from sarcoid patients compared to HD. Furthermore, we found a significant increase in NLRP3/GAPDH mRNA (p=0.0023) and a decrease in miR-223/U6 (p=0.0002) relative expression levels in sorted AM of sarcoid patients compared to HV. Compared to WT increased granuloma formation in lungs of miR-223 KO mice were detected, while NLRP3 KO mice had significantly less granuloma. Mice treated with the NLRP3 inhibitor MCC950 had significantly decreased pulmonary granuloma burden. Conclusion: In AM of sarcoid patients is the NLRP3 inflammasome chronically activated which may be related to low miR-223 levels. The novel NLRP3 inhibitor MCC950 may be a future treatment option in sarcoidosis.

: http://publica.fraunhofer.de/dokumente/N-559353.html