Department of Dermatology, Venerology and Allergology, Faculty of Medicine, Leipzig University, Germany.
Institute of Medical Physics and Biophysics; Faculty of Medicine, Leipzig University, Germany.
Theranostics. 2022 Jan 16;12(4):1659-1682. doi: 10.7150/thno.67174. eCollection 2022.
: In obesity the fine-tuned balance of macrophage phenotypes is disturbed towards a dominance of pro-inflammatory macrophages resulting in exacerbation and persistence of inflammation and impaired tissue repair. However, the underlying mechanisms are still poorly understood. : Impact of obesity on macrophage differentiation was studied in high fat diet induced obese and db/db mice during skin inflammation and wound repair, respectively. Mechanisms of S100A9-mediated effects on macrophage differentiation was studied on generated macrophages by genomic and proteomic approaches. The role of S100A9 on macrophage differentiation was investigated by pharmacological inhibition of S100A9 during skin inflammation and wound repair in obese and db/db mice. : We demonstrate an overexpression of S100A9 in conditions of obesity-associated disturbed macrophage differentiation in the skin. We show that saturated free fatty acids (SFA), which are increased in obesity, together with S100A9 induce TLR4 and inflammasome-dependent IL-1β release in macrophages which in turn amplifies S100A9 expression initiating a vicious cycle of sustained S100A9 overexpression in skin inflammation in obesity. We reveal a yet unrecognized impact of obesity-associated S100A9 overexpression on macrophage differentiation. S100A9 binding to TLR4 and activation of NFkB attenuates development of M2-like macrophages and induces pro-inflammatory functions in these cells. Consequently, inhibition of S100A9 restores disturbed M2-like macrophage differentiation in mouse models of obesity-associated skin inflammation and wound repair. Similarly, breaking the vicious cycle of S100A9 overexpression by dietary reduction of SFA restored M2-like macrophage activation. Improvement of skin inflammation and wound repair upon reduction of S100A9 by pharmacological inhibition or by reduction of SFA uncovers the pathogenic role of S100A9 overexpression in obesity. : This study identifies S100A9 as a previously unrecognized vital component in obesity-associated disturbed macrophage differentiation and subsequent impaired regulation of inflammation and wound repair. The findings open new opportunities for therapeutic implications for inflammatory diseases and wound repair in obesity.
在肥胖症中，巨噬细胞表型的精细平衡被扰乱，向促炎巨噬细胞占优势的方向发展，导致炎症加剧和持续，并损害组织修复。然而，其潜在机制仍知之甚少。
本研究分别在高脂肪饮食诱导的肥胖和 db/db 小鼠的皮肤炎症和伤口修复过程中，研究肥胖对巨噬细胞分化的影响。采用基因组和蛋白质组学方法研究 S100A9 介导的作用对巨噬细胞分化的机制。通过在肥胖和 db/db 小鼠的皮肤炎症和伤口修复过程中，用 S100A9 的药理学抑制剂抑制 S100A9，研究 S100A9 在巨噬细胞分化中的作用。
我们在肥胖相关的巨噬细胞分化紊乱的皮肤条件下，证实 S100A9 的过度表达。我们表明，在肥胖中增加的饱和游离脂肪酸 (SFA) 与 S100A9 一起诱导 TLR4 和炎性小体依赖性 IL-1β 在巨噬细胞中的释放，反过来又放大 S100A9 的表达，在肥胖的皮肤炎症中启动持续的 S100A9 过度表达的恶性循环。我们揭示了肥胖相关 S100A9 过度表达对巨噬细胞分化的尚未被认识的影响。S100A9 与 TLR4 结合并激活 NFkB ，减弱 M2 样巨噬细胞的发育，并诱导这些细胞的促炎功能。因此，抑制 S100A9 可恢复肥胖相关皮肤炎症和伤口修复的小鼠模型中紊乱的 M2 样巨噬细胞分化。同样，通过减少 SFA 来减少 S100A9 表达或通过减少 SFA 来打破 S100A9 过度表达的恶性循环，恢复 M2 样巨噬细胞的激活。通过药理学抑制或减少 SFA 减少 S100A9 改善皮肤炎症和伤口修复，揭示了 S100A9 过度表达在肥胖中的致病作用。
这项研究确定 S100A9 是肥胖相关的巨噬细胞分化紊乱和随后炎症调节受损以及伤口修复受损的一个以前未被认识的重要组成部分。这些发现为肥胖症中的炎症性疾病和伤口修复的治疗意义提供了新的机会。
