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Endothelial inflammation inhibitor screen

ABSTRACT: [placeholder] Endothelial inflammation is an important factor in endothelial dysfunction. TNFa and IFNg induce unique inflammation state in ECs, which is synergistically amplified when both are combined. Here we propose targeted inhibition of endothelial inflammation employing an unbiased proteomics drug inhibitor screen of NFKB and JAK/STAT targets. We show STAT6 regulates the expression of a wide range of angiogenic proteins. Inhibition of with JAK1 inhibitor itacitinib nullifies the IFNg inflammation response without off target proteomic effects. IKK2/STAT3 combined inhibition inhibited both inflammation states. Interestingly, the majority of TNFa+IFNg induced proteins could be inhibited by either JAK1 or IKK2/STAT3 inhibition, reiterating the synergetic nature of this inflammation state. Finally, we show the relation of VWF with inflammation. In conclusion we employ proteomic drug screen to assess potential drug candidates to inhibit endothelial inflammation, which highlights the feasibility of targeting the endothelium and provides an interesting outlook for future studies.

INSTRUMENT(S): timsTOF HT

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Endothelial Colony Forming Cell, Vasculature

SUBMITTER: Stijn Groten

LAB HEAD: Maartje van den Biggelaar

PROVIDER: PXD058294 | Pride | 2025-07-17

REPOSITORIES: Pride

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			Action	DRS
	20230908_SG_DrugPanel_C1_1_S2-H1_2610.d.ZIP	Other
	20230908_SG_DrugPanel_C1_2_S3-H1_2708.d.ZIP	Other
	20230908_SG_DrugPanel_C1_3_S1-H1_2806.d.ZIP	Other
	20230908_SG_DrugPanel_C2_1_S2-H2_2611.d.ZIP	Other
	20230908_SG_DrugPanel_C2_2_S3-H2_2709.d.ZIP	Other

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Project description:The role of Group IVA cytosolic phospholipase A2 (cPLA2M-NM-1) activation in regulating macrophage transcriptional responses to Candida albicans infection was investigated. cPLA2M-NM-1 releases arachidonic acid for the production of eicosanoids. In mouse resident peritoneal macrophages, prostacyclin, prostaglandin E2 and leukotriene C4 were produced within minutes of C. albicans addition before cyclooxygenase 2 expression. The production of TNFa was lower in C. albicans-stimulated cPLA2a+/+ than cPLA2a-/- macrophages due to an autocrine effect of prostaglandins that increased cAMP to a greater extent in cPLA2a+/+ than cPLA2a-/- macrophages. For global insight, differential gene expression in C. albicans-stimulated cPLA2a+/+ and cPLA2a-/- macrophages (3 h) was compared by microarray. cPLA2M-NM-1+/+ macrophages expressed 86 genes at lower levels and 181 genes at higher levels than cPLA2M-NM-1-/- macrophages (M-bM-^IM-%2-fold, p<0.05 ). Several pro-inflammatory genes were expressed at lower levels (Tnfa, Cx3cl1, Cd40, Ifng, several IFNg-inducible GTPases, Ccl5, Csf1, Edn1, CxCr7, Irf1, Irf4, Akna). Genes that dampen inflammation (Socs3, Il10, Crem, Stat3, Thbd, Thbs1, Abca1) and genes involved in host defense (Gja1, Csf3, Trem1, Hdc) were expressed at higher levels in cPLA2a+/+ macrophages. Representative genes expressed lower in cPLA2a+/+ macrophages (Tnfa and Csf1) were increased by treatment with a prostacyclin receptor antagonist and protein kinase A inhibitor, whereas genes expressed at higher levels (Crem, Nr4a2, Il10, Csf3) were suppressed. The results suggest that C. albicans stimulates an autocrine loop in macrophages involving cPLA2a, cyclooxygenase 1-derived prostaglandins and increased cAMP that globally effects expression of genes involved in host defense and inflammation. Resident peritoneal macrophages from Group IVA cytosolic phospholipase A2 (cPLA2a) +/+ and -/- mice were stimulated with Candida albicans (m.o.i. 2) for 3 hours and RNA isolated to evaluate the role of cPLA2a-derived lipid mediators on gene expression. Three independent experiments were analyzed.

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Endothelial inflammation inhibitor screen

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