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Progetto vincitore della Borsa di Studio SISA 2016 - M.P. Adorni

Effect of JAK-STAT inhibition on macrophage cholesterol metabolism and atherosclerosis

Maria Pia Adorni

Abstract:

Background/Rationale. Systemic inflammatory and autoimmune diseases are associated with accelerated atherosclerosis and increased cardiovascular risk. This link involves monocyte activation, increased macrophage lipid deposition and augmented inflammation in vascular intima. Macrophages counteract cholesterol accumulation by the efflux process (CE), occurring through four main mechanisms and allowing cholesterol transfer to extracellular acceptors, mainly high-density lipoproteins (HDL). In macrophages, cholesterol metabolism and inflammation are strictly linked, contributing to the pathogenesis of atherosclerosis. We and others showed that serum CE capacity (CEC) is impaired in patients with inflammatory and autoimmune diseases and drugs can be differently influence cholesterol metabolism on the macrophage side. The Janus Kinase/signal transducers and activators of transcription (JAK/STAT) pathway is an essential intracellular signaling mechanism regulating inflammatory and immune responses. Recently it has been shown that the induction of JAK/STAT signaling pathway is pro-atherogenic.

Objectives of the project. The aim of this study is to assess the effect of JAK-STAT inhibition on cholesterol metabolism and inflammatory function in macrophage exposed to serum of healthy subjects and autoimmune patients.

Methods and research strategies. The effect of JAK-STAT inhibition, obtained with tofaticinib, will be evaluated on: cholesterol efflux, free cholesterol distribution and foam cells formation measured by isotopic techniques, cholesterol accumulation by fluorimetric assay and cytokines secretion using ELISA kits.

Expected results. The results will contribute to define JAK-STAT signaling pathway

Presentazione del progetto vincitore di Borsa di Studio SISA - 2016