Department of Gastrointestinal Surgery, First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China.
Department of Clinical Laboratory, First Affiliated Hospital of Bengbu Medical College, Bengbu, China.
J Crohns Colitis. 2022 Nov 23;16(11):1762-1776. doi: 10.1093/ecco-jcc/jjac087.
Hypertrophic mesenteric adipose tissue [htMAT] is involved in the disease progression of Crohn's disease [CD] through expressing proinflammatory adipokines from dysfunctional adipocytes by unknown mechanism. Adipocyte function is affected by dynamic adipose tissue extracellular matrix [ECM] remodelling that is mainly mediated by macrophages, and our study aimed to reveal whether aberrant ECM remodelling was present in CD-htMAT and its effects on adipocyte dysfunction, as well as the mechanism.
ECM remodelling was examined in MAT samples from CD patients and controls. Mice with dinitrobenzene sulphonic acid [DNBS]-induced colitis were used in vivo study, and lipopolysaccharide [LPS]-induced remodelling behaviour in macrophages was examined in vitro. Macrophages or TLR4 inhibition were used to analyse ECM remodelling mechanisms and their effects on adipocyte function.
Aberrant ECM remodelling: was observed in CD-htMAT, which was characterised by a widened and deformed ECM structure accompanied by dysregulated matrix synthesis and degradation; served as a reservoir for inflammatory factors/cells dominated by macrophages; and was involved in adipocyte dysfunction. In addition, macrophages were the main source of ECM remodelling regulatory factors with activation of Toll-like receptor 4 [TLR4] in htMAT. In vivo, macrophage depletion or TLR4 inhibition largely attenuated mesenteric ECM remodelling while improving mesenteric adipocyte dysfunction during chronic enteritis. In vitro, antagonizing TLR4 significantly inhibited LPS-induced macrophage ECM remodelling behavior.
The aberrant ECM remodelling in CD-htMAT contributed to mesenteric adipocyte dysfunction, which may be caused at least partly by TLR4-mediated macrophage remodelling behavior. Inhibiting ECM remodelling may be a potential therapeutic strategy for CD.
肥大肠系膜脂肪组织 [htMAT] 通过功能失调的脂肪细胞表达促炎脂肪因子参与克罗恩病 [CD] 的疾病进展，但具体机制尚不清楚。脂肪细胞功能受动态脂肪组织细胞外基质 [ECM] 重塑的影响，而 ECM 重塑主要由巨噬细胞介导，我们的研究旨在揭示 CD-htMAT 是否存在异常 ECM 重塑及其对脂肪细胞功能障碍的影响和机制。
检测 CD 患者和对照者的 MAT 样本中的 ECM 重塑。使用二硝基苯磺酸 [DNBS] 诱导的结肠炎小鼠进行体内研究，并在体外研究脂多糖 [LPS] 诱导的巨噬细胞重塑行为。使用巨噬细胞或 TLR4 抑制来分析 ECM 重塑机制及其对脂肪细胞功能的影响。
在 CD-htMAT 中观察到异常的 ECM 重塑，其特征是 ECM 结构变宽和变形，伴随基质合成和降解失调；充当以巨噬细胞为主的炎症因子/细胞的储库；并参与脂肪细胞功能障碍。此外，巨噬细胞是 ECM 重塑调节因子的主要来源，htMAT 中的 Toll 样受体 4 [TLR4] 被激活。在体内，巨噬细胞耗竭或 TLR4 抑制在慢性肠炎期间在很大程度上减轻了肠系膜 ECM 重塑，同时改善了肠系膜脂肪细胞功能障碍。在体外，拮抗 TLR4 显著抑制 LPS 诱导的巨噬细胞 ECM 重塑行为。
CD-htMAT 中异常的 ECM 重塑导致肠系膜脂肪细胞功能障碍，这至少部分可能是由 TLR4 介导的巨噬细胞重塑行为引起的。抑制 ECM 重塑可能是 CD 的一种潜在治疗策略。
