LRRK2 Kinase Function Regulates NLRC4 Inflammasome Activity and Thereby Modulates Intestinal Inflammation

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Presentation Time: 11:30 AM - 12:45 PM
Poster Board Number: B191
Abstract ID: 4312

Presenting Author:
Sharmina Deloer , Postdoctoral Fellow at NIAID, NIH

Abstract:

The LRRK2 protein associated with increased risk of IBD. Recently described, this protein influences NLRC4 inflammasome phosphorylation. This LRRK2 function, however, has uncertain significance since it is not clear how NLRC4 phosphorylation affects NLRC4 inflammasome function.This study utilizes commercially available LRRK2 inhibitors, to clarify this knowledge gap. In vitro studies showed that inhibition of LRRK2 kinase activity inhibits both its binding to NLRC4 and phosphorylation upon activation with needle protein, thus establishing that LRRK2 has an indispensable role for NLRC4 phosphorylation. later using THP-1 cells with ASC deletion or human PBMC-derived dendritic cells with shRNA ASC- KD showed that ASC deficiency retards NLRC4 phosphorylation. Finally, we found that inhibition of NLRC4 phosphorylation by LRRK2 inhibitors has a major negative effect on NLRC4 mediated IL-1b cleavage but, surprisingly, it has minor effect on IL-18 cleavage.  This indicated that IL-1b expression requires ASC-caspase binding whereas IL-18 expression does not. Next, systemic administration of NLRC4 activator (flagellin protein) caused increased intestinal permeability and that co-administration of inhibitor reversed the increased permeability. These findings concluded that inhibition of IL-1b production with the preservation of IL-18 via LRRK2 kinase inhibition blocks the potentially harmful effects of NLRC4 activity on intestinal permeability during intestinal inflammation.