Bromodomain Inhibitors Modulate FcγR-Mediated Mononuclear Phagocyte Activation and Chemotaxis
IgG antibodies form immune complexes (IC) that propagate inflammation and tissue damage in autoimmune diseases such as systemic lupus erythematosus. IgG IC engage Fcγ receptors (FcγR) on mononuclear phagocytes (MNP), leading to widespread changes in gene expression that mediate antibody effector fun...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-05-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.885101/full |
| _version_ | 1818246208491094016 |
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| author | Gemma D. Banham Colin Y. C. Lee Colin Y. C. Lee John R. Ferdinand Rebeccah J. Matthews Chenzhi Jing Nicholas Smithers Rab K. Prinjha Menna R. Clatworthy Menna R. Clatworthy |
| author_facet | Gemma D. Banham Colin Y. C. Lee Colin Y. C. Lee John R. Ferdinand Rebeccah J. Matthews Chenzhi Jing Nicholas Smithers Rab K. Prinjha Menna R. Clatworthy Menna R. Clatworthy |
| author_sort | Gemma D. Banham |
| collection | DOAJ |
| description | IgG antibodies form immune complexes (IC) that propagate inflammation and tissue damage in autoimmune diseases such as systemic lupus erythematosus. IgG IC engage Fcγ receptors (FcγR) on mononuclear phagocytes (MNP), leading to widespread changes in gene expression that mediate antibody effector function. Bromodomain and extra-terminal domain (BET) proteins are involved in governing gene transcription. We investigated the capacity of BET protein inhibitors (iBET) to alter IgG FcγR-mediated MNP activation. We found that iBET dampened IgG IC-induced pro-inflammatory gene expression and decreased activating FcγR expression on MNPs, reducing their ability to respond to IgG IC. Despite FcγR downregulation, iBET-treated macrophages demonstrated increased phagocytosis of protein antigen, IgG IC, and apoptotic cells. iBET also altered cell morphology, generating more amoeboid MNPs with reduced adhesion. iBET treatment impaired chemotaxis towards a CCL19 gradient in IC-stimulated dendritic cells (DC) in vitro, and inhibited IC-induced DC migration to draining lymph nodes in vivo, in a DC-intrinsic manner. Altogether, our data show that iBET modulates FcγR-mediated MNP activation and migration, revealing the therapeutic potential of BET protein inhibition in antibody-mediated diseases. |
| first_indexed | 2024-12-12T14:45:09Z |
| format | Article |
| id | doaj.art-e322c97f57e446f2ad778535777f905e |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-12T14:45:09Z |
| publishDate | 2022-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-e322c97f57e446f2ad778535777f905e2022-12-22T00:21:07ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-05-011310.3389/fimmu.2022.885101885101Bromodomain Inhibitors Modulate FcγR-Mediated Mononuclear Phagocyte Activation and ChemotaxisGemma D. Banham0Colin Y. C. Lee1Colin Y. C. Lee2John R. Ferdinand3Rebeccah J. Matthews4Chenzhi Jing5Nicholas Smithers6Rab K. Prinjha7Menna R. Clatworthy8Menna R. Clatworthy9Molecular Immunity Unit, Department of Medicine, Medical Research Council Laboratory of Molecular Biology, University of Cambridge, Cambridge, United KingdomMolecular Immunity Unit, Department of Medicine, Medical Research Council Laboratory of Molecular Biology, University of Cambridge, Cambridge, United KingdomCellular Genetics, Wellcome Sanger Institute, Cambridge, United KingdomMolecular Immunity Unit, Department of Medicine, Medical Research Council Laboratory of Molecular Biology, University of Cambridge, Cambridge, United KingdomMolecular Immunity Unit, Department of Medicine, Medical Research Council Laboratory of Molecular Biology, University of Cambridge, Cambridge, United KingdomMolecular Immunity Unit, Department of Medicine, Medical Research Council Laboratory of Molecular Biology, University of Cambridge, Cambridge, United KingdomEpinova DPU, Immuno-Inflammation Centre of Excellence for Drug Discovery, GlaxoSmithKline, Medicines Research Centre, Stevenage, United KingdomEpinova DPU, Immuno-Inflammation Centre of Excellence for Drug Discovery, GlaxoSmithKline, Medicines Research Centre, Stevenage, United KingdomMolecular Immunity Unit, Department of Medicine, Medical Research Council Laboratory of Molecular Biology, University of Cambridge, Cambridge, United KingdomCellular Genetics, Wellcome Sanger Institute, Cambridge, United KingdomIgG antibodies form immune complexes (IC) that propagate inflammation and tissue damage in autoimmune diseases such as systemic lupus erythematosus. IgG IC engage Fcγ receptors (FcγR) on mononuclear phagocytes (MNP), leading to widespread changes in gene expression that mediate antibody effector function. Bromodomain and extra-terminal domain (BET) proteins are involved in governing gene transcription. We investigated the capacity of BET protein inhibitors (iBET) to alter IgG FcγR-mediated MNP activation. We found that iBET dampened IgG IC-induced pro-inflammatory gene expression and decreased activating FcγR expression on MNPs, reducing their ability to respond to IgG IC. Despite FcγR downregulation, iBET-treated macrophages demonstrated increased phagocytosis of protein antigen, IgG IC, and apoptotic cells. iBET also altered cell morphology, generating more amoeboid MNPs with reduced adhesion. iBET treatment impaired chemotaxis towards a CCL19 gradient in IC-stimulated dendritic cells (DC) in vitro, and inhibited IC-induced DC migration to draining lymph nodes in vivo, in a DC-intrinsic manner. Altogether, our data show that iBET modulates FcγR-mediated MNP activation and migration, revealing the therapeutic potential of BET protein inhibition in antibody-mediated diseases.https://www.frontiersin.org/articles/10.3389/fimmu.2022.885101/fullBET inhibitorssystemic lupus erythematosus (SLE)Fcγ-receptordendritic cell chemotaxisantibody-mediated inflammation |
| spellingShingle | Gemma D. Banham Colin Y. C. Lee Colin Y. C. Lee John R. Ferdinand Rebeccah J. Matthews Chenzhi Jing Nicholas Smithers Rab K. Prinjha Menna R. Clatworthy Menna R. Clatworthy Bromodomain Inhibitors Modulate FcγR-Mediated Mononuclear Phagocyte Activation and Chemotaxis Frontiers in Immunology BET inhibitors systemic lupus erythematosus (SLE) Fcγ-receptor dendritic cell chemotaxis antibody-mediated inflammation |
| title | Bromodomain Inhibitors Modulate FcγR-Mediated Mononuclear Phagocyte Activation and Chemotaxis |
| title_full | Bromodomain Inhibitors Modulate FcγR-Mediated Mononuclear Phagocyte Activation and Chemotaxis |
| title_fullStr | Bromodomain Inhibitors Modulate FcγR-Mediated Mononuclear Phagocyte Activation and Chemotaxis |
| title_full_unstemmed | Bromodomain Inhibitors Modulate FcγR-Mediated Mononuclear Phagocyte Activation and Chemotaxis |
| title_short | Bromodomain Inhibitors Modulate FcγR-Mediated Mononuclear Phagocyte Activation and Chemotaxis |
| title_sort | bromodomain inhibitors modulate fcγr mediated mononuclear phagocyte activation and chemotaxis |
| topic | BET inhibitors systemic lupus erythematosus (SLE) Fcγ-receptor dendritic cell chemotaxis antibody-mediated inflammation |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.885101/full |
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