Pharmacological Inhibition of Amyloidogenic APP Processing and Knock-Down of APP in Primary Human Macrophages Impairs the Secretion of Cytokines
It has been previously shown that the amyloid precursor protein (APP) support the innate immune defense as an immune receptor. Amyloid β (Aβ) peptides seem to have properties of an antimicrobial peptide and can act as opsonines. In APP-deficient mouse models, a reduced secretion of cytokines has bee...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2020-09-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2020.01967/full |
| _version_ | 1818289060179869696 |
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| author | Philipp Spitzer Matthias Walter Caroline Göth Timo Jan Oberstein Philipp Linning Hans-Joachim Knölker Johannes Kornhuber Juan Manuel Maler |
| author_facet | Philipp Spitzer Matthias Walter Caroline Göth Timo Jan Oberstein Philipp Linning Hans-Joachim Knölker Johannes Kornhuber Juan Manuel Maler |
| author_sort | Philipp Spitzer |
| collection | DOAJ |
| description | It has been previously shown that the amyloid precursor protein (APP) support the innate immune defense as an immune receptor. Amyloid β (Aβ) peptides seem to have properties of an antimicrobial peptide and can act as opsonines. In APP-deficient mouse models, a reduced secretion of cytokines has been observed. Still, it is unclear whether this can be attributed to the lack of APP or to the missing secretion of Aβ peptides. We inhibited the secretion of Aβ peptides in primary human monocyte derived macrophages with the γ-secretase inhibitor N-[N-(3,5-Difluorophenacetyl)-L-alanyl]-S-phenylglycine-t-butyl-ester (DAPT) or the β-secretase inhibitor GL-189. Alternatively, we knocked down APP by transfection with siRNA. We measured tumor necrosis factor α (TNFα), interleukin 6 (IL-6) and interleukin (IL-10) by enzyme linked immunosorbent assay (ELISA) and evaluated the phagocytotic activity by flow cytometry. We observed reduced concentrations of TNFα and IL-6 in the media of APPk/d macrophages and after inhibition of the β-, or γ-secretase, especially after additional immunological activation with lipopolysaccharide (LPS). Secretion of IL-10 was increased after pharmacological inhibition of APP processing when the macrophages were not immunologically activated but was decreased during LPS-induced inflammation in APPk/d macrophages. No changes of the phagocytotic activity were observed. We conclude that macrophage APP and Aβ peptides support the initiation of an immune response and are involved in the regulation of TNFα, IL-6, and IL-10 secretion by human monocyte-derived macrophages. |
| first_indexed | 2024-12-13T02:06:16Z |
| format | Article |
| id | doaj.art-0e37a06f21524da1b433f46479b2637c |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-13T02:06:16Z |
| publishDate | 2020-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-0e37a06f21524da1b433f46479b2637c2022-12-22T00:03:07ZengFrontiers Media S.A.Frontiers in Immunology1664-32242020-09-011110.3389/fimmu.2020.01967532812Pharmacological Inhibition of Amyloidogenic APP Processing and Knock-Down of APP in Primary Human Macrophages Impairs the Secretion of CytokinesPhilipp Spitzer0Matthias Walter1Caroline Göth2Timo Jan Oberstein3Philipp Linning4Hans-Joachim Knölker5Johannes Kornhuber6Juan Manuel Maler7Department of Psychiatry and Psychotherapy, Friedrich-Alexander-Universität Erlangen-Nürnberg, University Hospital Erlangen, Erlangen, GermanyDepartment of Psychiatry and Psychotherapy, Friedrich-Alexander-Universität Erlangen-Nürnberg, University Hospital Erlangen, Erlangen, GermanyDepartment of Psychiatry and Psychotherapy, Friedrich-Alexander-Universität Erlangen-Nürnberg, University Hospital Erlangen, Erlangen, GermanyDepartment of Psychiatry and Psychotherapy, Friedrich-Alexander-Universität Erlangen-Nürnberg, University Hospital Erlangen, Erlangen, GermanyFaculty of Chemistry, Technische Universität Dresden, Dresden, GermanyFaculty of Chemistry, Technische Universität Dresden, Dresden, GermanyDepartment of Psychiatry and Psychotherapy, Friedrich-Alexander-Universität Erlangen-Nürnberg, University Hospital Erlangen, Erlangen, GermanyDepartment of Psychiatry and Psychotherapy, Friedrich-Alexander-Universität Erlangen-Nürnberg, University Hospital Erlangen, Erlangen, GermanyIt has been previously shown that the amyloid precursor protein (APP) support the innate immune defense as an immune receptor. Amyloid β (Aβ) peptides seem to have properties of an antimicrobial peptide and can act as opsonines. In APP-deficient mouse models, a reduced secretion of cytokines has been observed. Still, it is unclear whether this can be attributed to the lack of APP or to the missing secretion of Aβ peptides. We inhibited the secretion of Aβ peptides in primary human monocyte derived macrophages with the γ-secretase inhibitor N-[N-(3,5-Difluorophenacetyl)-L-alanyl]-S-phenylglycine-t-butyl-ester (DAPT) or the β-secretase inhibitor GL-189. Alternatively, we knocked down APP by transfection with siRNA. We measured tumor necrosis factor α (TNFα), interleukin 6 (IL-6) and interleukin (IL-10) by enzyme linked immunosorbent assay (ELISA) and evaluated the phagocytotic activity by flow cytometry. We observed reduced concentrations of TNFα and IL-6 in the media of APPk/d macrophages and after inhibition of the β-, or γ-secretase, especially after additional immunological activation with lipopolysaccharide (LPS). Secretion of IL-10 was increased after pharmacological inhibition of APP processing when the macrophages were not immunologically activated but was decreased during LPS-induced inflammation in APPk/d macrophages. No changes of the phagocytotic activity were observed. We conclude that macrophage APP and Aβ peptides support the initiation of an immune response and are involved in the regulation of TNFα, IL-6, and IL-10 secretion by human monocyte-derived macrophages.https://www.frontiersin.org/article/10.3389/fimmu.2020.01967/fullamyloid precursor proteinamyloidAbetaAlzheimercytokineimmune system |
| spellingShingle | Philipp Spitzer Matthias Walter Caroline Göth Timo Jan Oberstein Philipp Linning Hans-Joachim Knölker Johannes Kornhuber Juan Manuel Maler Pharmacological Inhibition of Amyloidogenic APP Processing and Knock-Down of APP in Primary Human Macrophages Impairs the Secretion of Cytokines Frontiers in Immunology amyloid precursor protein amyloid Abeta Alzheimer cytokine immune system |
| title | Pharmacological Inhibition of Amyloidogenic APP Processing and Knock-Down of APP in Primary Human Macrophages Impairs the Secretion of Cytokines |
| title_full | Pharmacological Inhibition of Amyloidogenic APP Processing and Knock-Down of APP in Primary Human Macrophages Impairs the Secretion of Cytokines |
| title_fullStr | Pharmacological Inhibition of Amyloidogenic APP Processing and Knock-Down of APP in Primary Human Macrophages Impairs the Secretion of Cytokines |
| title_full_unstemmed | Pharmacological Inhibition of Amyloidogenic APP Processing and Knock-Down of APP in Primary Human Macrophages Impairs the Secretion of Cytokines |
| title_short | Pharmacological Inhibition of Amyloidogenic APP Processing and Knock-Down of APP in Primary Human Macrophages Impairs the Secretion of Cytokines |
| title_sort | pharmacological inhibition of amyloidogenic app processing and knock down of app in primary human macrophages impairs the secretion of cytokines |
| topic | amyloid precursor protein amyloid Abeta Alzheimer cytokine immune system |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2020.01967/full |
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