Development of a novel, cell-based chemical screen to identify inhibitors of intraphagosomal lipolysis in macrophages.

Cytometry. Part a : the Journal of the International Society for Analytical Cytology
Brian C VanderVenRobin M Yates

Abstract

Macrophages play a central role in tissue homeostasis and the immune system. Their primary function is to internalize cellular debris and microorganisms for degradation within their phagosomes. In this context, their capacity to process and sequester lipids such as triacylglycerides and cholesteryl esters makes them key players in circulatory diseases, such as atheroclerosis. To discover new inhibitors of lipolytic processing within the phagosomal system of the macrophage, we have developed a novel, cell-based assay suitable for high-throughput screening. We employed particles carrying a fluorogenic triglyceride substrate and a calibration fluor to screen for inhibitors of phagosomal lipolysis. A panel of secondary assays were employed to discriminate between lipase inhibitors and compounds that perturbed general phagosomal trafficking events. This process enabled us to identify a new structural class of pyrazole-methanone compounds that directly inhibit lysosomal and lipoprotein lipase activity.

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Citations

Dec 26, 2013·The Journal of Cell Biology·Akriti PrasharMauricio R Terebiznik
Jul 20, 2010·Cell Host & Microbe·David G RussellKyle H Rohde
Jun 16, 2017·The Journal of Biological Chemistry·Maidina TuohetahuntilaJ Bernd Helms
Feb 11, 2014·Current Protocols in Immunology·Maria PodinovskaiaDavid G Russell
Apr 28, 2019·The EMBO Journal·Manman GuoMatthias Trost
May 24, 2018·The EMBO Journal·Anetta HärtlovaMaximiliano G Gutierrez
Apr 20, 2018·JCI Insight·Shiny NairMadhav V Dhodapkar
Nov 2, 2019·Nanomedicine : Nanotechnology, Biology, and Medicine·Douglas O EscrivaniBartira Rossi-Bergmann

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