Department of Pediatrics, Darby Children's Research Institute, Medical University of South Carolina, Charleston, SC 29425, USA.
Department of Pediatrics, Darby Children's Research Institute, Medical University of South Carolina, Charleston, SC 29425, USA; Department of Health and Human Physiology, and the Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242, USA.
Cell Rep. 2024 Nov 26;43(11):114925. doi: 10.1016/j.celrep.2024.114925. Epub 2024 Oct 30.
Although cancer cachexia is classically characterized as a systemic inflammatory disorder, emerging evidence indicates that weight loss also associates with local tissue inflammation. We queried the regulation of this inflammation and its causality to cachexia by exploring skeletal muscle, whose atrophy strongly associates with poor outcomes. Using multiple mouse models and patient samples, we show that cachectic muscle is marked by enhanced innate immunity. Nuclear factor κB (NF-κB) activity in multiple cells, including satellite cells, myofibers, and fibro-adipogenic progenitors, promotes macrophage expansion equally derived from infiltrating monocytes and resident cells. Moreover, NF-κB-activated cells and macrophages undergo crosstalk; NF-κB cells recruit macrophages to inhibit regeneration and promote atrophy but, interestingly, also protect myofibers, while macrophages stimulate NF-κB cells to sustain an inflammatory feedforward loop. Together, we propose that NF-κB functions in multiple cells in the muscle microenvironment to stimulate macrophages that both promote and protect against muscle wasting in cancer.
虽然癌症恶病质通常被认为是一种系统性炎症紊乱，但新出现的证据表明，体重减轻也与局部组织炎症有关。我们通过探索骨骼肌来研究这种炎症的调节及其与恶病质的因果关系，因为骨骼肌萎缩与不良预后密切相关。使用多种小鼠模型和患者样本，我们发现恶病质肌肉表现出增强的固有免疫。包括卫星细胞、肌纤维和纤维脂肪祖细胞在内的多种细胞中的核因子 κB（NF-κB）活性促进了巨噬细胞的扩张，这些巨噬细胞同样来自浸润的单核细胞和固有细胞。此外，NF-κB 激活的细胞和巨噬细胞之间发生串扰；NF-κB 细胞招募巨噬细胞以抑制再生并促进萎缩，但有趣的是，也保护肌纤维，而巨噬细胞则刺激 NF-κB 细胞维持炎症的正反馈循环。总之，我们提出 NF-κB 在肌肉微环境中的多种细胞中发挥作用，刺激巨噬细胞，促进和防止癌症中的肌肉消耗。
