Inhibition of LRRK2 Kinase Activity with a Novel Inhibitor (CS 82) Inhibits NLRC4 Inflammasome Activation and Reduces Intestinal Inflammation Severity
Year: 2023
Type: conference-abstract
Abstract: In the last twenty years Leucine Rich Repeat Kinase 2 (LRRK2) has received immense attention due to its association with several diseases, for example, neurodegenerative disease PD (Parkinson’s Disease), inflammatory bowel disease (IBD), Crohn’s disease (CD), infectious disease Leprosy etc. Not only do genetic mutations make this protein a hotspot for various diseases but also it shows some pleotropic characteristics which might influence several diseases. LRRK2 directly controls several proteins for example Rab GTPase proteins, NLRC4 inflammasomes etc. NLRC4 also showed correlation with auto-inflammatory diseases such as CD, Macrophage Activation Syndrome (MAS) etc. Here we report that NLRC4 dependent cytokine storm retarded through LRRK2 kinase inhibition as well as reduces severity of intestinal inflammation. For LRRK2 kinase inhibition a novel kinase inhibitor (Termed CS 82) has been used. In vitro studies disclosed that this inhibitor suppress LRRK2 phosphorylation as well as its ability to phosphorylate the LRRK2 targets, Rab 10 and 12; in addition, they suppress human dendritic cell production of TNFa stimulated by several known LRRK2 activators including the Dectin-1-ligand, zymosan- depleted S. cerevisiae extract. Finally, the inhibitors exhibited powerful suppression of the ability of LRRK2 to mediate NLRC4 inflammasome production of IL-1beta. LRRK2 deficiency showed inhibitor has no effect on NLRC4 dependent IL-1b cytokine productions. These findings suggest that inhibition of LRRK2 kinase activity retarded NLRC4 inflammasome activation which reduces IL-1b cytokine productions and intestinal inflammation severity.
Source: The Journal of Immunology
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W4385688127