Inhibition of BET Proteins Regulates Fcγ Receptor Function and Reduces Inflammation in Rheumatoid Arthritis
Overactivation of immune responses is a hallmark of autoimmune disease pathogenesis. This includes the heightened production of inflammatory cytokines such as Tumor Necrosis Factor α (TNFα), and the secretion of autoantibodies such as isotypes of rheumatoid factor (RF) and anticitrullinated protein...
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MDPI AG
2023-04-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/8/7623 |
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| author | Divya Shankar Giovanna Merchand-Reyes Nathaniel J. Buteyn Ramasamy Santhanam Huiqing Fang Krishan Kumar Xiaokui Mo Latha P. Ganesan Wael Jarjour Jonathan P. Butchar Susheela Tridandapani |
| author_facet | Divya Shankar Giovanna Merchand-Reyes Nathaniel J. Buteyn Ramasamy Santhanam Huiqing Fang Krishan Kumar Xiaokui Mo Latha P. Ganesan Wael Jarjour Jonathan P. Butchar Susheela Tridandapani |
| author_sort | Divya Shankar |
| collection | DOAJ |
| description | Overactivation of immune responses is a hallmark of autoimmune disease pathogenesis. This includes the heightened production of inflammatory cytokines such as Tumor Necrosis Factor α (TNFα), and the secretion of autoantibodies such as isotypes of rheumatoid factor (RF) and anticitrullinated protein antibody (ACPA). Fcγ receptors (FcγR) expressed on the surface of myeloid cells bind Immunoglobulin G (IgG) immune complexes. Recognition of autoantigen-antibody complexes by FcγR induces an inflammatory phenotype that results in tissue damage and further escalation of the inflammatory response. Bromodomain and extra-terminal protein (BET) inhibition is associated with reduced immune responses, making the BET family a potential therapeutic target for autoimmune diseases such as rheumatoid arthritis (RA). In this paper, we examined the BET inhibitor PLX51107 and its effect on regulating FcγR expression and function in RA. PLX51107 significantly downregulated expression of FcγRIIa, FcγRIIb, FcγRIIIa, and the common γ-chain, FcϵR1-γ, in both healthy donor and RA patient monocytes. Consistent with this, PLX51107 treatment attenuated signaling events downstream of FcγR activation. This was accompanied by a significant decrease in phagocytosis and TNFα production. Finally, in a collagen-induced arthritis model, PLX51107-treatment reduced FcγR expression in vivo accompanied by a significant reduction in footpad swelling. These results suggest that BET inhibition is a novel therapeutic approach that requires further exploration as a treatment for patients with RA. |
| first_indexed | 2024-03-11T04:54:48Z |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T04:54:48Z |
| publishDate | 2023-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-28c113ee41bb49b39ff93a1607121ef32023-11-17T19:43:15ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-04-01248762310.3390/ijms24087623Inhibition of BET Proteins Regulates Fcγ Receptor Function and Reduces Inflammation in Rheumatoid ArthritisDivya Shankar0Giovanna Merchand-Reyes1Nathaniel J. Buteyn2Ramasamy Santhanam3Huiqing Fang4Krishan Kumar5Xiaokui Mo6Latha P. Ganesan7Wael Jarjour8Jonathan P. Butchar9Susheela Tridandapani10College of Medicine, The Ohio State University, Columbus, OH 43210, USADepartment of Internal Medicine, The Ohio State University, Columbus, OH 43210, USAVan Andel Institute, Grand Rapids, MI 49503, USADepartment of Internal Medicine, The Ohio State University, Columbus, OH 43210, USADepartment of Internal Medicine, The Ohio State University, Columbus, OH 43210, USADepartment of Internal Medicine, The Ohio State University, Columbus, OH 43210, USADepartment of Biomedical Informatics, The Ohio State University, Columbus, OH 43210, USADepartment of Internal Medicine, The Ohio State University, Columbus, OH 43210, USADepartment of Internal Medicine, The Ohio State University, Columbus, OH 43210, USADepartment of Internal Medicine, The Ohio State University, Columbus, OH 43210, USADepartment of Internal Medicine, The Ohio State University, Columbus, OH 43210, USAOveractivation of immune responses is a hallmark of autoimmune disease pathogenesis. This includes the heightened production of inflammatory cytokines such as Tumor Necrosis Factor α (TNFα), and the secretion of autoantibodies such as isotypes of rheumatoid factor (RF) and anticitrullinated protein antibody (ACPA). Fcγ receptors (FcγR) expressed on the surface of myeloid cells bind Immunoglobulin G (IgG) immune complexes. Recognition of autoantigen-antibody complexes by FcγR induces an inflammatory phenotype that results in tissue damage and further escalation of the inflammatory response. Bromodomain and extra-terminal protein (BET) inhibition is associated with reduced immune responses, making the BET family a potential therapeutic target for autoimmune diseases such as rheumatoid arthritis (RA). In this paper, we examined the BET inhibitor PLX51107 and its effect on regulating FcγR expression and function in RA. PLX51107 significantly downregulated expression of FcγRIIa, FcγRIIb, FcγRIIIa, and the common γ-chain, FcϵR1-γ, in both healthy donor and RA patient monocytes. Consistent with this, PLX51107 treatment attenuated signaling events downstream of FcγR activation. This was accompanied by a significant decrease in phagocytosis and TNFα production. Finally, in a collagen-induced arthritis model, PLX51107-treatment reduced FcγR expression in vivo accompanied by a significant reduction in footpad swelling. These results suggest that BET inhibition is a novel therapeutic approach that requires further exploration as a treatment for patients with RA.https://www.mdpi.com/1422-0067/24/8/7623FcγRrheumatoid arthritismonocytesBET inhibition |
| spellingShingle | Divya Shankar Giovanna Merchand-Reyes Nathaniel J. Buteyn Ramasamy Santhanam Huiqing Fang Krishan Kumar Xiaokui Mo Latha P. Ganesan Wael Jarjour Jonathan P. Butchar Susheela Tridandapani Inhibition of BET Proteins Regulates Fcγ Receptor Function and Reduces Inflammation in Rheumatoid Arthritis International Journal of Molecular Sciences FcγR rheumatoid arthritis monocytes BET inhibition |
| title | Inhibition of BET Proteins Regulates Fcγ Receptor Function and Reduces Inflammation in Rheumatoid Arthritis |
| title_full | Inhibition of BET Proteins Regulates Fcγ Receptor Function and Reduces Inflammation in Rheumatoid Arthritis |
| title_fullStr | Inhibition of BET Proteins Regulates Fcγ Receptor Function and Reduces Inflammation in Rheumatoid Arthritis |
| title_full_unstemmed | Inhibition of BET Proteins Regulates Fcγ Receptor Function and Reduces Inflammation in Rheumatoid Arthritis |
| title_short | Inhibition of BET Proteins Regulates Fcγ Receptor Function and Reduces Inflammation in Rheumatoid Arthritis |
| title_sort | inhibition of bet proteins regulates fcγ receptor function and reduces inflammation in rheumatoid arthritis |
| topic | FcγR rheumatoid arthritis monocytes BET inhibition |
| url | https://www.mdpi.com/1422-0067/24/8/7623 |
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