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Members of the Bromodomain Extra-Terminal Domain (BET) family — BRD2, BRD3, BRD4, and BRDT — are key regulators of transcription. BET inhibition is associated with reduced immune responses, making the BET family a potential therapeutic target for autoimmune diseases, including rheumatoid arthritis (RA). Autoimmune disease pathogenesis is dependent on the overactivation of immune responses. This includes the heightened production of inflammatory cytokines, like TNFα, and secretion of autoantibodies, such as isotypes of rheumatoid factor and anticitrullinated protein antibody (ACPA), which target healthy tissues. Fcγ receptors (FcγR) expressed on the surface of myeloid cells bind Immunoglobulin G (IgG) immune complexes; FcγRIa, FcγRIIa, FcγRIIIa are activating FcγR, whereas FcγRIIb is an inhibitory FcγR. Recognition of autoantibodies by FcγRs induces an inflammatory phenotype that results in tissue damage and further escalation of the inflammatory response.

Here we examine a novel BET inhibitor, PLX51107, and its effect on regulating FcγR expression and function in RA. PLX51107 substantially upregulated FcγRIa and downregulated FcγRIIa, FcγRIIb, FcγRIIIa, and FcϵR1-γ (γ-chain) — FcγRIa and FcγRIIIa's associated signaling protein — mRNA and protein levels in healthy donor and RA monocytes. Consistent with this, PLX51107 treatment decreased phagocytic and rosetting indexes, FcγR-mediated NF-κB, AKT, and MAPK signaling, and TNFα production, indicating the attenuation of the immune response.

Our findings suggest that BET inhibition may have clinical relevance in the treatment of RA. Further studies are critical to explore how BET inhibition mechanistically regulates FcγRs to alleviate their mediated inflammatory responses, and to determine if BET inhibition, via PLX51107, is therapeutic in a murine model of RA.