Targeting KAT2A inhibits inflammatory macrophage activation and rheumatoid arthritis through epigenetic and metabolic reprogramming

Abstract

Epigenetic regulation of inflammatory macrophages governs inflammation initiation and resolution in the pathogenesis of rheumatoid arthritis (RA). Nevertheless, the mechanisms underlying macrophage‐mediated arthritis injuries remain largely obscure. Here, we found that increased expression of lysine acetyltransferase 2A (KAT2A) in synovial tissues was closely correlated with inflammatory joint immunopathology in both RA patients and experimental arthritis mice. Administration of MB‐3, the KAT2A‐specific chemical inhibitor, significantly ameliorated the synovitis and bone destruction in collagen‐induced arthritis model. Both pharmacological inhibition and siRNA silencing of KAT2A, not only suppressed innate stimuli‐triggered proinflammatory gene (such as Il1b and Nlrp3) transcription but also impaired NLR family pyrin domain containing 3 (NLRP3) inflammasome activation in vivo and in vitro. Mechanistically, KAT2A facilitated macrophage glycolysis reprogramming through suppressing nuclear factor‐erythroid 2‐related factor 2 (NRF2) activity as well as downstream antioxidant molecules, which supported histone 3 lysine 9 acetylation (H3K9ac) and limited NRF2‐mediated transcriptional repression of proinflammatory genes. Our study proves that acetyltransferase KAT2A licenses metabolic and epigenetic reprogramming for NLRP3 inflammasome activation in inflammatory macrophages, thereby targeting KAT2A represents a potential therapeutic approach for patients suffering from RA and relevant inflammatory diseases.

Regulation of metabolic microenvironment with a nanocomposite hydrogel for improved bone fracture healing

“…Nrf2 activation facilitates metabolic reprogramming and mitochondrial fusion, leading to a suppressed inflammatory response [ 32 ]. Zhang et al indicated that expression of lysine acetyltransferase 2A (KAT2A) in macrophages suppressed Nrf2 activity, resulting in an increased inflammatory response and bone destruction in rheumatoid arthritis [ 33 ]. The metabolism of BMSCs can also be remodeled to finetune their functions.…”

Rheumatoid arthritis: pathogenesis and therapeutic advances

“…With the clarification of epigenetic mechanisms in RA, key enzymes that regulate important biological processes such as DNA methylation, RNA m 6 A, and histone modification might become potential therapeutic targets for RA. The functions of azacitidine targeted for DNMT, 189 anacardic acid and MB‐3 targeted for HAT, 96 , 190 GSK‐J4 targeted for KDM, 191 MS‐275 targeted for HDAC, 192 I‐BET151 targeted for BRD4 193 have been verified in animal studies.…”

“…Our previous research elucidated that KAT2A was overexpressed in RA synovium, and pharmacological inhibition of KAT2A significantly alleviated inflammation in collagen‐induced arthritis (CIA) mice. 96 …”

Noval advance of histone modification in inflammatory skin diseases and related treatment methods

“…This correlation is attributed to the promotion of Il1b and Nlrp3 transcription through histone H3K9ac modification and the inhibition of NRF2 transcription repressor activity by KAT2A. Additionally, another type of HAT, CBP/p300, enhances cytokine expression by increasing the levels of H3K27a ( 34 ). Another type of HAT, known as CBP/p300, facilitates the expression of cytokines by upregulating the abundance of H3K27ac ( 35 ).…”