Group V secreted phospholipase A2 is upregulated by IL-4 in human macrophages and mediates phagocytosis via hydrolysis of ethanolamine phospholipids.
Studies on the heterogeneity and plasticity of macrophage populations led to the identification of two major polarization states: classically activated macrophages or M1, induced by IFN-γ plus LPS, and alternatively activated macrophages, induced by IL-4. We studied the expression of multiple phospholipase A2 enzymes in human macrophages and the effect that polarization of the cells has on their levels. At least 11 phospholipase A2 genes were found at significant levels in human macrophages, as detected by quantitative PCR. None of these exhibited marked changes after treating the cells with IFN-γ plus LPS. However, macrophage treatment with IL-4 led to strong upregulation of the secreted group V phospholipase A2 (sPLA2-V), both at the mRNA and protein levels. In parallel with increasing sPLA2-V expression levels, IL-4-treated macrophages exhibited increased phagocytosis of yeast-derived zymosan and bacteria, and we show that both events are causally related, because cells deficient in sPLA2-V exhibited decreased phagocytosis, and cells overexpressing the enzyme manifested higher rates of phagocytosis. Mass spectrometry analyses of lipid changes in the IL-4-treated macrophages suggest that ethanolamine lysophospholipid (LPE) is an sPLA2-V-derived product that may be involved in regulating phagocytosis. Cellular levels of LPE are selectively maintained by sPLA2-V. By supplementing sPLA2-V-deficient cells with LPE, phagocytosis of zymosan or bacteria was fully restored in IL-4-treated cells. Collectively, our results show that sPLA2-V is required for efficient phagocytosis by IL-4-treated human macrophages and provide evidence that sPLA2-V-derived LPE is involved in the process.
Instituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Científicas, Universidad de Valladolid, 47003 Valladolid, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, 28029 Madrid, Spain; and.
Julio M
JM
Rubio
Instituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Científicas, Universidad de Valladolid, 47003 Valladolid, Spain; Laboratorio de Investigación en Proteínas, Facultad de Ciencias Exactas y Naturales y Agrimensura, Universidad Nacional del Nordeste, 3400 Corrientes, Argentina.
Juan P
JP
Rodríguez
Instituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Científicas, Universidad de Valladolid, 47003 Valladolid, Spain;
Luis
L
Gil-de-Gómez
Instituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Científicas, Universidad de Valladolid, 47003 Valladolid, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, 28029 Madrid, Spain; and.
Carlos
C
Guijas
Instituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Científicas, Universidad de Valladolid, 47003 Valladolid, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, 28029 Madrid, Spain; and.
María A
MA
Balboa
Instituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Científicas, Universidad de Valladolid, 47003 Valladolid, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, 28029 Madrid, Spain; and jbalsinde@ibgm.uva.es.
Jesús
J
Balsinde
D005786:Gene Expression Regulation / Q000187:drug effects; D054505:Group V Phospholipases A2 / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D064368:Healthy Volunteers; D006801:Humans; D006868:Hydrolysis; D015847:Interleukin-4 / Q000378:metabolism* / Q000494:pharmacology; D007527:Isoenzymes; D050356:Lipid Metabolism; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D008297:Male; D010587:Phagocytosis / Q000187:drug effects / Q000235:genetics* / Q000276:immunology*; D010714:Phosphatidylethanolamines / Q000378:metabolism* / Q000494:pharmacology
D007527:Isoenzymes; D010714:Phosphatidylethanolamines; D015847:Interleukin-4; D054505:Group V Phospholipases A2