PMID- 37108786
OWN - NLM
STAT- MEDLINE
DCOM- 20230502
LR  - 20240423
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 24
IP  - 8
DP  - 2023 Apr 21
TI  - Inhibition of BET Proteins Regulates Fcgamma Receptor Function and Reduces 
      Inflammation in Rheumatoid Arthritis.
LID - 10.3390/ijms24087623 [doi]
LID - 7623
AB  - Overactivation of immune responses is a hallmark of autoimmune disease 
      pathogenesis. This includes the heightened production of inflammatory cytokines 
      such as Tumor Necrosis Factor alpha (TNFalpha), and the secretion of autoantibodies such 
      as isotypes of rheumatoid factor (RF) and anticitrullinated protein antibody 
      (ACPA). Fcgamma receptors (FcgammaR) expressed on the surface of myeloid cells bind 
      Immunoglobulin G (IgG) immune complexes. Recognition of autoantigen-antibody 
      complexes by FcgammaR 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 FcgammaR expression and function in 
      RA. PLX51107 significantly downregulated expression of FcgammaRIIa, FcgammaRIIb, 
      FcgammaRIIIa, and the common gamma-chain, FcϵR1-gamma, in both healthy donor and RA patient 
      monocytes. Consistent with this, PLX51107 treatment attenuated signaling events 
      downstream of FcgammaR activation. This was accompanied by a significant decrease in 
      phagocytosis and TNFalpha production. Finally, in a collagen-induced arthritis model, 
      PLX51107-treatment reduced FcgammaR 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.
FAU - Shankar, Divya
AU  - Shankar D
AUID- ORCID: 0009-0003-5216-3258
AD  - College of Medicine, The Ohio State University, Columbus, OH 43210, USA.
FAU - Merchand-Reyes, Giovanna
AU  - Merchand-Reyes G
AD  - Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, 
      USA.
FAU - Buteyn, Nathaniel J
AU  - Buteyn NJ
AD  - Van Andel Institute, Grand Rapids, MI 49503, USA.
FAU - Santhanam, Ramasamy
AU  - Santhanam R
AD  - Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, 
      USA.
FAU - Fang, Huiqing
AU  - Fang H
AD  - Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, 
      USA.
FAU - Kumar, Krishan
AU  - Kumar K
AUID- ORCID: 0000-0003-4406-2644
AD  - Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, 
      USA.
FAU - Mo, Xiaokui
AU  - Mo X
AD  - Department of Biomedical Informatics, The Ohio State University, Columbus, OH 
      43210, USA.
FAU - Ganesan, Latha P
AU  - Ganesan LP
AD  - Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, 
      USA.
FAU - Jarjour, Wael
AU  - Jarjour W
AD  - Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, 
      USA.
FAU - Butchar, Jonathan P
AU  - Butchar JP
AD  - Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, 
      USA.
FAU - Tridandapani, Susheela
AU  - Tridandapani S
AD  - Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, 
      USA.
LA  - eng
GR  - P30 CA016058/CA/NCI NIH HHS/United States
GR  - R01 CA203584/CA/NCI NIH HHS/United States
GR  - R01 CA2034584/CA/NCI NIH HHS/United States
PT  - Journal Article
DEP - 20230421
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - 0 (Receptors, IgG)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 0 (Nerve Tissue Proteins)
SB  - IM
MH  - Humans
MH  - *Arthritis, Rheumatoid/metabolism
MH  - Inflammation/metabolism
MH  - Monocytes/metabolism
MH  - *Receptors, IgG/metabolism
MH  - Tumor Necrosis Factor-alpha/metabolism
MH  - Nerve Tissue Proteins/metabolism
PMC - PMC10143512
OTO - NOTNLM
OT  - BET inhibition
OT  - FcgammaR
OT  - monocytes
OT  - rheumatoid arthritis
COIS- All authors declare that no conflict of interest exists regarding this 
      manuscript.
EDAT- 2023/04/28 06:41
MHDA- 2023/05/01 06:42
PMCR- 2023/04/21
CRDT- 2023/04/28 01:30
PHST- 2023/03/10 00:00 [received]
PHST- 2023/03/30 00:00 [revised]
PHST- 2023/04/19 00:00 [accepted]
PHST- 2023/05/01 06:42 [medline]
PHST- 2023/04/28 06:41 [pubmed]
PHST- 2023/04/28 01:30 [entrez]
PHST- 2023/04/21 00:00 [pmc-release]
AID - ijms24087623 [pii]
AID - ijms-24-07623 [pii]
AID - 10.3390/ijms24087623 [doi]
PST - epublish
SO  - Int J Mol Sci. 2023 Apr 21;24(8):7623. doi: 10.3390/ijms24087623.