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Regulation of Leucine-Rich Repeat Kinase 2 by inflammation and IL-4

ABSTRACT: Mutations in Leucine-Rich Repeat protein Kinase 2 (LRRK2) are associated with Parkinson's Disease (PD) and Crohn's Disease (CD), but the regulation of LRRK2 during inflammation remains relatively unexplored. Here we developed a flow cytometry-based assay to assess LRRK2 activity in individual cells and created an EGFP-Lrrk2-knock-in reporter mouse to analyse cell-specific LRRK2 expression. Using these tools, we catalogued LRRK2 levels and activity in splenic and intestinal immune cells. Inflammation increased LRRK2 expression and activity in B-cells, immature neutrophils and immature monocytes, but decreased these in dendritic cells and eosinophils. In mature neutrophils, inflammation stimulated activity but reduced LRRK2 expression. A kinase-activating PD-associated LRRK2-R1441C mutation exacerbated inflammation-induced activation of LRRK2 specifically in monocytes and macrophages without affecting LRRK2 levels. Finally, we identified IL-4 as a novel factor that upregulated LRRK2 expression and activity in B-cells,replicating inflammatory effects observed in vivo. Our findings provide valuable new insights into the regulation of the LRRK2 pathway in immune cells, crucial for understanding LRRK2 and its therapeutic potential in inflammatory diseases such as CD.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): B Cell, Lymph Node

SUBMITTER: Andrew Howden

LAB HEAD: Dr Mahima Swamy

PROVIDER: PXD056827 | Pride | 2025-03-04

REPOSITORIES: Pride

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Project description:The role of propionate-induced rearrangement of membrane proteins in the formation of the virulent phenotype of Crohn's Disease-associated adherent-invasive Escherichia coli. Adhesive-invasive Escherichia coli (AIEC) were first isolated from the ileal mucosa of a patient with Crohn's disease (CD) which is a severe chronic immune-mediated granulomatous inflammatory disease of the gastrointestinal tract. It turned out that they are able to successfully penetrate the mucin layer, overcome the epithelial barrier, and also survive and multiply inside macrophage. Bacteria with such properties were assigned to a special group of pathobiont adhesive-invasive E. coli. AIEC activity is accompanied by the release of pro-inflammatory cytokines, i.e. surviving and multiplying inside macrophages, they enhance the inflammatory process. The role of AIEC in the onset or chronicity of CD is not well-defined. However, it has been proposed that these bacteria could trigger the onset of the inflammatory process as a result of the invasion of intestinal epithelial cells, and then, due to their survival within macrophages, they could stimulate chronic inflammation and granuloma developmen. Pathogens use a variety of mechanisms, including the induction of inflammation, the direct or indirect destruction of commensal species, and the use of alternative carbon sources to survive. AIEC are shown to be able to utilize ethanolamine and propanediol, which are formed during the catabolism of phospholipids, fucose or rhamnose, propionate and other metabolites. Metabolic plasticity is thought to allow AIEC to act as an opportunistic pathogen in conditions of intestinal inflammation. We have previously shown that passage of AIEC from a CD patient (CD isolate) on M9 minimal medium supplemented with sodium propionate (PA) as a carbon source leads to a strong increase, and passage on M9 medium supplemented with glucose, on the contrary, leads to a significant decrease in adhesive-invasive properties and ability to survive in macrophages. We were able to compare the isogenic CD isolate in two states: virulent with high adhesive-invasive activity and ability to survive in macrophages, and non-virulent, when these properties are lost. In contrast to the CD isolate, passage of the laboratory strain K12 Mg1655 on the M9 medium supplemented with PA did not cause a similar effect. We performed a comparative proteomic analysis of membrane fractions isolated from ZvL2-PA and ZvL2-GLU using LC-MS. The laboratory strain K12 Mg1655 was used as a control.

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	IL4_alone_BR1.raw	Raw
	IL4_alone_BR2.raw	Raw
	IL4_alone_BR3.raw	Raw
	IL4_alone_BR4.raw	Raw
	Naive_BR1.raw	Raw

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Regulation of Leucine-Rich Repeat Kinase 2 by inflammation and IL-4

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