Choline Glycerophospholipid-Derived Prostaglandins Attenuate TNFα Gene Expression in Macrophages via a cPLA<sub>2</sub>α/COX-1 Pathway
Macrophages are professional antigen presenting cells with intense phagocytic activity, strategically distributed in tissues and cavities. These cells are capable of responding to a wide variety of innate inflammatory stimuli, many of which are signaled by lipid mediators. The distribution of arachi...
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MDPI AG
2021-02-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/10/2/447 |
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| author | Alma M. Astudillo Juan P. Rodríguez Carlos Guijas Julio M. Rubio María A. Balboa Jesús Balsinde |
| author_facet | Alma M. Astudillo Juan P. Rodríguez Carlos Guijas Julio M. Rubio María A. Balboa Jesús Balsinde |
| author_sort | Alma M. Astudillo |
| collection | DOAJ |
| description | Macrophages are professional antigen presenting cells with intense phagocytic activity, strategically distributed in tissues and cavities. These cells are capable of responding to a wide variety of innate inflammatory stimuli, many of which are signaled by lipid mediators. The distribution of arachidonic acid (AA) among glycerophospholipids and its subsequent release and conversion into eicosanoids in response to inflammatory stimuli such as zymosan, constitutes one of the most studied models. In this work, we used liquid and/or gas chromatography coupled to mass spectrometry to study the changes in the levels of membrane glycerophospholipids of mouse peritoneal macrophages and the implication of group IVA cytosolic phospholipase A<sub>2</sub> (cPLA<sub>2</sub>α) in the process. In the experimental model used, we observed that the acute response of macrophages to zymosan stimulation involves solely the cyclooxygenase-1 (COX-1), which mediates the rapid synthesis of prostaglandins E<sub>2</sub> and I<sub>2</sub>. Using pharmacological inhibition and antisense inhibition approaches, we established that cPLA<sub>2</sub>α is the enzyme responsible for AA mobilization. Zymosan stimulation strongly induced the hydrolysis of AA-containing choline glycerophospholipids (PC) and a unique phosphatidylinositol (PI) species, while the ethanolamine-containing glycerophospholipids remained constant or slightly increased. Double-labeling experiments with <sup>3</sup>H- and <sup>14</sup>C-labeled arachidonate unambiguously demonstrated that PC is the major, if not the exclusive source, of AA for prostaglandin E<sub>2</sub> production, while both PC and PI appeared to contribute to prostaglandin I<sub>2</sub> synthesis. Importantly, in this work we also show that the COX-1-derived prostaglandins produced during the early steps of macrophage activation restrict tumor necrosis factor-α production. Collectively, these findings suggest new approaches and targets to the selective inhibition of lipid mediator production in response to fungal infection. |
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| language | English |
| last_indexed | 2024-03-09T00:44:07Z |
| publishDate | 2021-02-01 |
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| spelling | doaj.art-cc21c5731ee94d8ab7e1759328b2e7972023-12-11T17:41:49ZengMDPI AGCells2073-44092021-02-0110244710.3390/cells10020447Choline Glycerophospholipid-Derived Prostaglandins Attenuate TNFα Gene Expression in Macrophages via a cPLA<sub>2</sub>α/COX-1 PathwayAlma M. Astudillo0Juan P. Rodríguez1Carlos Guijas2Julio M. Rubio3María A. Balboa4Jesús Balsinde5Instituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Científicas (CSIC), 47003 Valladolid, SpainInstituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Científicas (CSIC), 47003 Valladolid, SpainInstituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Científicas (CSIC), 47003 Valladolid, SpainInstituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Científicas (CSIC), 47003 Valladolid, SpainInstituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Científicas (CSIC), 47003 Valladolid, SpainInstituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Científicas (CSIC), 47003 Valladolid, SpainMacrophages are professional antigen presenting cells with intense phagocytic activity, strategically distributed in tissues and cavities. These cells are capable of responding to a wide variety of innate inflammatory stimuli, many of which are signaled by lipid mediators. The distribution of arachidonic acid (AA) among glycerophospholipids and its subsequent release and conversion into eicosanoids in response to inflammatory stimuli such as zymosan, constitutes one of the most studied models. In this work, we used liquid and/or gas chromatography coupled to mass spectrometry to study the changes in the levels of membrane glycerophospholipids of mouse peritoneal macrophages and the implication of group IVA cytosolic phospholipase A<sub>2</sub> (cPLA<sub>2</sub>α) in the process. In the experimental model used, we observed that the acute response of macrophages to zymosan stimulation involves solely the cyclooxygenase-1 (COX-1), which mediates the rapid synthesis of prostaglandins E<sub>2</sub> and I<sub>2</sub>. Using pharmacological inhibition and antisense inhibition approaches, we established that cPLA<sub>2</sub>α is the enzyme responsible for AA mobilization. Zymosan stimulation strongly induced the hydrolysis of AA-containing choline glycerophospholipids (PC) and a unique phosphatidylinositol (PI) species, while the ethanolamine-containing glycerophospholipids remained constant or slightly increased. Double-labeling experiments with <sup>3</sup>H- and <sup>14</sup>C-labeled arachidonate unambiguously demonstrated that PC is the major, if not the exclusive source, of AA for prostaglandin E<sub>2</sub> production, while both PC and PI appeared to contribute to prostaglandin I<sub>2</sub> synthesis. Importantly, in this work we also show that the COX-1-derived prostaglandins produced during the early steps of macrophage activation restrict tumor necrosis factor-α production. Collectively, these findings suggest new approaches and targets to the selective inhibition of lipid mediator production in response to fungal infection.https://www.mdpi.com/2073-4409/10/2/447arachidonic acideicosanoidsphospholipid remodelingphospholipase A<sub>2</sub>inflammationmonocytes/macrophages |
| spellingShingle | Alma M. Astudillo Juan P. Rodríguez Carlos Guijas Julio M. Rubio María A. Balboa Jesús Balsinde Choline Glycerophospholipid-Derived Prostaglandins Attenuate TNFα Gene Expression in Macrophages via a cPLA<sub>2</sub>α/COX-1 Pathway Cells arachidonic acid eicosanoids phospholipid remodeling phospholipase A<sub>2</sub> inflammation monocytes/macrophages |
| title | Choline Glycerophospholipid-Derived Prostaglandins Attenuate TNFα Gene Expression in Macrophages via a cPLA<sub>2</sub>α/COX-1 Pathway |
| title_full | Choline Glycerophospholipid-Derived Prostaglandins Attenuate TNFα Gene Expression in Macrophages via a cPLA<sub>2</sub>α/COX-1 Pathway |
| title_fullStr | Choline Glycerophospholipid-Derived Prostaglandins Attenuate TNFα Gene Expression in Macrophages via a cPLA<sub>2</sub>α/COX-1 Pathway |
| title_full_unstemmed | Choline Glycerophospholipid-Derived Prostaglandins Attenuate TNFα Gene Expression in Macrophages via a cPLA<sub>2</sub>α/COX-1 Pathway |
| title_short | Choline Glycerophospholipid-Derived Prostaglandins Attenuate TNFα Gene Expression in Macrophages via a cPLA<sub>2</sub>α/COX-1 Pathway |
| title_sort | choline glycerophospholipid derived prostaglandins attenuate tnfα gene expression in macrophages via a cpla sub 2 sub α cox 1 pathway |
| topic | arachidonic acid eicosanoids phospholipid remodeling phospholipase A<sub>2</sub> inflammation monocytes/macrophages |
| url | https://www.mdpi.com/2073-4409/10/2/447 |
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