KAT3B-mediated succinylation of DERL3 suppresses osteogenic differentiation by promoting M1/M2 macrophage polarization.

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY Biochemical pharmacology Pub Date : 2024-12-21 DOI:10.1016/j.bcp.2024.116724

Bohan Yu, Yanan Qiao, Xi Sun, Yue Yin

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Abstract

Periodontitis is a chronic inflammatory disease influenced by macrophage polarization. Additionally, succinylation-enriched Porphyromonas gingivalis is a pathogenic factor of periodontitis. However, the role of succinylation in the pathogenesis of periodontitis remains unclear. This study aimed to investigate the effects of a succinyltransferase KAT3B on macrophage polarization, osteogenic differentiation, and the molecular mechanism. Macrophages RAW264.7 were cocultured with MC3T3-E1-differentiated osteoblasts, and macrophage polarization and osteogenic differentiation were evaluated. iTRAQ-based proteomic analysis identified that DERL3 was highly expressed in lipopolysaccharide (LPS)-treated MC3T3-E1 cells. The TLR4/MyD88 pathway is closely related to inflammatory response. Thus, the succinylation of DERL3 and the TLR4/MyD88 pathway were assessed using immunoblotting. The results showed that KAT3B-mediated succinylation was increased in LPS-treated MC3T3-E1 cells and patients with periodontitis. Knockdown of KAT3B inhibited macrophage M1-like polarization and promoted M2-like polarization, thereby promoting osteogenic differentiation in LPS-treated osteoblasts. Mechanically, overexpression of KAT3B promoted the succinylation of DERL3 and stabilized this protein, thereby upregulating DERL3 expression. Rescue experiments showed that DERL3 reversed the promotion of osteogenic differentiation and M2/M1 macrophage polarization caused by KAT3B knockdown. Moreover, DERL3 activated the TLR4/MyD88 pathway, and inhibition of this pathway reversed macrophage polarization and osteogenesis mediated by DERL3. In vivo experiments showed that KAT3B knockdown attenuated experimental periodontitis in rats. In conclusion, silencing of KAT3B promotes osteogenic differentiation by inducing M2/M1 macrophage polarization through the succinylation DERL3, which regulates the TLR4/MyD88 pathway, thereby attenuating periodontitis. These findings suggest that KAT3B may be a promising therapeutic target for periodontitis.

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kat3b介导的DERL3琥珀酰化通过促进M1/M2巨噬细胞极化抑制成骨分化。

牙周炎是一种受巨噬细胞极化影响的慢性炎症性疾病。此外，琥珀酰化富集的牙龈卟啉单胞菌是牙周炎的致病因素。然而，琥珀酰化在牙周炎发病机制中的作用尚不清楚。本研究旨在探讨琥珀基转移酶KAT3B对巨噬细胞极化、成骨分化的影响及其分子机制。将巨噬细胞RAW264.7与mc3t3 - e1分化成骨细胞共培养，观察巨噬细胞极化和成骨分化情况。基于itraq的蛋白质组学分析发现，DERL3在脂多糖（LPS）处理的MC3T3-E1细胞中高度表达。TLR4/MyD88通路与炎症反应密切相关。因此，使用免疫印迹法评估DERL3和TLR4/MyD88通路的琥珀酰化。结果显示，在lps处理的MC3T3-E1细胞和牙周炎患者中，kat3b介导的琥珀酰化水平升高。敲低KAT3B抑制巨噬细胞m1样极化，促进m2样极化，从而促进lps处理成骨细胞的成骨分化。机械上，KAT3B的过表达促进了DERL3的琥珀酰化并稳定了该蛋白，从而上调了DERL3的表达。救援实验表明，DERL3逆转了KAT3B敲低导致的成骨分化和M2/M1巨噬细胞极化的促进。此外，DERL3激活了TLR4/MyD88通路，抑制该通路逆转了DERL3介导的巨噬细胞极化和成骨。体内实验表明，KAT3B基因敲低可减轻大鼠实验性牙周炎。综上所述，KAT3B的沉默通过琥珀酰化DERL3诱导M2/M1巨噬细胞极化，从而调节TLR4/MyD88通路，从而促进成骨分化，从而减轻牙周炎。这些发现提示KAT3B可能是治疗牙周炎的一个有希望的靶点。

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来源期刊

Biochemical pharmacology 医学-药学

CiteScore

10.30

自引率

1.70%

发文量

420

审稿时长

17 days

期刊介绍： Biochemical Pharmacology publishes original research findings, Commentaries and review articles related to the elucidation of cellular and tissue function(s) at the biochemical and molecular levels, the modification of cellular phenotype(s) by genetic, transcriptional/translational or drug/compound-induced modifications, as well as the pharmacodynamics and pharmacokinetics of xenobiotics and drugs, the latter including both small molecules and biologics. The journal''s target audience includes scientists engaged in the identification and study of the mechanisms of action of xenobiotics, biologics and drugs and in the drug discovery and development process. All areas of cellular biology and cellular, tissue/organ and whole animal pharmacology fall within the scope of the journal. Drug classes covered include anti-infectives, anti-inflammatory agents, chemotherapeutics, cardiovascular, endocrinological, immunological, metabolic, neurological and psychiatric drugs, as well as research on drug metabolism and kinetics. While medicinal chemistry is a topic of complimentary interest, manuscripts in this area must contain sufficient biological data to characterize pharmacologically the compounds reported. Submissions describing work focused predominately on chemical synthesis and molecular modeling will not be considered for review. While particular emphasis is placed on reporting the results of molecular and biochemical studies, research involving the use of tissue and animal models of human pathophysiology and toxicology is of interest to the extent that it helps define drug mechanisms of action, safety and efficacy.