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A phosphatidylinositol species acutely generated by activated macrophages regulates innate immune responses

AuthorsGil-de-Gómez, Luis ; Astudillo, Alma M. ; Meana, Clara ; Rubio, Julio M. ; Guijas, Carlos ; Balboa, María A. ; Balsinde, Jesús
Issue Date2013
PublisherAmerican Association of Immunologists
CitationJournal of Immunology 190(10): 5169-5177 (2013)
AbstractActivation of macrophages with stimuli of the innate immune response results in the intense remodeling of arachidonate-containing phospholipids, leading to the mobilization of large quantities of this fatty acid for conversion into biologically active eicosanoids. As a consequence of this process, the arachidonate levels in membrane phospholipids markedly decrease. We have applied mass spectrometry–based lipid profiling to study the levels of arachidonate-containing phospholipids under inflammatory activation of macrophages. We identify an unusual inositol phospholipid molecule, PI(20:4/20:4), the levels of which do not decrease but actually increase by 300% after activation of the macrophages. PI(20:4/20:4) is formed and degraded rapidly, suggesting a role for this molecule in regulating cell signaling events. Using a metabolipidomic approach consisting in exposing the cells to deuterium-labeled arachidonate at the time they are exposed to stimuli, we show that PI(20:4/20:4) biosynthesis occurs via the sequential incorporation of arachidonate, first into the sn-2 position of a preformed phosphatidylinositol (PI) molecule, followed by the rapid introduction of a second arachidonate moiety into the sn-1 position. Generation requires the participation of cytosolic phospholipase A2α and CoA-dependent acyltransferases. PI(20:4/20:4) formation is also detected in vivo in murine peritonitis exudates. Elevating the intracellular concentration of PI(20:4/20:4) by introducing the lipid into the cells results in enhancement of the microbicidal capacity of macrophages, as measured by reactive oxygen metabolite production and lysozyme release. These findings suggest that PI(20:4/20:4) is a novel bioactive inositol phospholipid molecule that regulates innate immune responses in macrophages.
Publisher version (URL)http://dx.doi.org/10.4049/jimmunol.1203494
Identifiersdoi: 10.4049/jimmunol.1203494
issn: 0022-1767
e-issn: 1550-6606
Appears in Collections:(IBGM) Artículos
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