Department of Gastroenterology, Second Affiliated Hospital of Nanchang University, 330006 Nanchang, Jiangxi, China.
Front Biosci (Landmark Ed). 2024 Nov 19;29(11):387. doi: 10.31083/j.fbl2911387.
Macrophage polarization is involved in the development of ulcerative colitis (UC). This study investigated the mechanism by which high mobility group box-1 protein (HMGB1) regulates macrophage polarization through metabolic reprogramming, thereby contributing to the pathogenesis of UC.
Dextran sulfate sodium (DSS) was used to induce colitis in mice. RAW264.7 cells were polarized to M1 or M2 macrophages by stimulating with lipopolysaccharide (LPS)/interferon-γ (IFN-γ) or Interleukin-4 (IL-4), respectively. Macrophage infiltration and distribution within colon tissue were assessed by immunohistochemistry and flow cytometry. Glycolysis, fatty acid oxidation (FAO), and inflammatory factors were evaluated using relevant reagent kits. Chromatin Immunoprecipitation (ChIP) and luciferase reporter experiments were performed to study the regulation of Carnitine palmitoyltransferase 1A (Cpt1a) promoter transcriptional activity by HMGB1.
The mouse UC model showed upregulated HMGB1 and increased macrophage infiltration. Overexpression of HMGB1 promoted M1 macrophage polarization, increased glycolysis, and reduced FAO, whereas knockdown of HMGB1 promoted M2 macrophage polarization, reduced glycolysis, and increased FAO. HMGB1 negatively regulated Cpt1a expression by inhibiting transcription of the Cpt1a promoter. Knockdown of Cpt1a reversed the effects of small interfering RNA targeting HMGB1 (si-HMGB1) on macrophage metabolism and polarization. Administration of adeno-associated virus (AAV)-shHMGB1 caused a reduction in UC symptoms and inflammation.
HMGB1 modulates macrophage metabolism in UC by inhibiting Cpt1a expression, leading to increased M1 polarization. This provides a theoretical basis for the clinical application of HMGB1 inhibitors in the treatment of UC.
巨噬细胞极化参与溃疡性结肠炎（UC）的发生发展。本研究旨在探讨高迁移率族蛋白 1（HMGB1）通过代谢重编程调节巨噬细胞极化的机制，从而促进 UC 的发病机制。
采用葡聚糖硫酸钠（DSS）诱导小鼠结肠炎。通过脂多糖（LPS）/干扰素-γ（IFN-γ）或白细胞介素-4（IL-4）分别刺激 RAW264.7 细胞向 M1 或 M2 巨噬细胞极化。通过免疫组织化学和流式细胞术评估结肠组织中巨噬细胞的浸润和分布。使用相关试剂盒评估糖酵解、脂肪酸氧化（FAO）和炎症因子。通过染色质免疫沉淀（ChIP）和荧光素酶报告基因实验研究 HMGB1 对肉毒碱棕榈酰转移酶 1A（Cpt1a）启动子转录活性的调节。
UC 模型小鼠中 HMGB1 表达上调，巨噬细胞浸润增加。HMGB1 过表达促进 M1 型巨噬细胞极化，增加糖酵解，减少 FAO，而 HMGB1 敲低促进 M2 型巨噬细胞极化，减少糖酵解，增加 FAO。HMGB1 通过抑制 Cpt1a 启动子转录负调控 Cpt1a 表达。沉默 Cpt1a 逆转了针对 HMGB1 的小干扰 RNA（si-HMGB1）对巨噬细胞代谢和极化的影响。腺相关病毒（AAV）-shHMGB1 的给药导致 UC 症状和炎症减轻。
HMGB1 通过抑制 Cpt1a 表达调节 UC 中的巨噬细胞代谢，导致 M1 极化增加。这为 HMGB1 抑制剂在 UC 治疗中的临床应用提供了理论依据。
