Inflammatory stimuli alter bone marrow composition and compromise bone health in the malnourished host.
Inflammatory stimuli alter bone marrow composition and compromise bone health in the malnourished host.
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DOI：
10.3389/fimmu.2022.846246
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发表时间：
2022
影响因子：
7.3
通讯作者：
中科院分区：
文献类型：
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炎症在儿童营养不良的发病机制中发挥作用。我们研究了营养不良和炎症挑战对骨髓成分和骨骼健康的影响。我们研究了一种已建立的小鼠模型，该模型在基线时和在用细菌脂多糖（LPS）（革兰氏阴性细菌败血症的替代品）或杜氏利什曼原虫（内脏利什曼病的病因）进行急性炎症攻击后出现中度急性营养不良。这两种感染都会导致营养不良儿童的显着发病率和死亡率。在这两种刺激中，LPS 引起更明显的骨髓变化，这种变化在营养不良的小鼠中放大。 LPS 攻击导致营养不良小鼠骨髓中炎症细胞因子表达（Il1b、Il6 和 Tnf）增加、炎症小体激活和炎症单核细胞积聚。 Csfr1-LysMcre-DT 营养不良小鼠中炎症单核细胞的消耗显着减少了 LPS 攻击后炎症小体的激活和 IL1-ß 的产生。炎症挑战还导致营养不良小鼠中间充质干细胞 (MSC) 的扩增、骨髓肥胖以及与脂肪生成相关的基因（Pparg、Adipoq 和 Srbp1）的表达增加。这表明，在营养不良的宿主中，炎症挑战促进骨髓间充质干细胞向脂肪细胞谱系分化，而不是向成骨细胞分化。与成骨细胞潜力降低同时，骨吸收破骨细胞增加，破骨细胞活性增强，炎症基因上调，以及参与破骨细胞分化和激活的IL-1B。由此导致的骨形成减弱和骨吸收增加将导致与营养不良相关的骨脆性。最后，我们评估了在营养缺乏的饮食中用富含 omega-3 脂肪酸的脂质（鱼油）替代富含 omega-6 脂肪酸的脂质（玉米油）的效果。接受脂多糖（LPS）挑战的营养不良小鼠接受膳食鱼油后，炎症细胞因子和Rankl表达降低，骨髓中破骨细胞分化和活化减少。这项工作表明，炎症挑战对骨髓的负面影响在营养不良的宿主中被放大。增加膳食中 omega-3 脂肪酸的摄入量可能是减少营养不良儿童炎症和改善骨骼健康的一种方法。
Inflammation has a role in the pathogenesis of childhood malnutrition. We investigated the effect of malnutrition and inflammatory challenge on bone marrow composition and bone health. We studied an established murine model of moderate acute malnutrition at baseline and after acute inflammatory challenge with bacterial lipopolysaccharide (LPS), a surrogate of Gram-negative bacterial sepsis, or Leishmania donovani, the cause of visceral leishmaniasis. Both of these infections cause significant morbidity and mortality in malnourished children. Of the 2 stimuli, LPS caused more pronounced bone marrow changes that were amplified in malnourished mice. LPS challenge led to increased inflammatory cytokine expression (Il1b, Il6, and Tnf), inflammasome activation, and inflammatory monocyte accumulation in the bone marrow of malnourished mice. Depletion of inflammatory monocytes in Csfr1-LysMcre-DT malnourished mice significantly reduced the inflammasome activation and IL1-ß production after LPS challenge. The inflammatory challenge also led to increased expansion of mesenchymal stem cells (MSCs), bone marrow adiposity, and expression of genes (Pparg, Adipoq, and Srbp1) associated with adipogenesis in malnourished mice. This suggests that inflammatory challenge promotes differentiation of BM MSCs toward the adipocyte lineage rather than toward bone-forming osteoblasts in the malnourished host. Concurrent with this reduced osteoblastic potential there was an increase in bone-resorbing osteoclasts, enhanced osteoclast activity, upregulation of inflammatory genes, and IL-1B involved in osteoclast differentiation and activation. The resulting weakened bone formation and increased bone resorption would contribute to the bone fragility associated with malnutrition. Lastly, we evaluated the effect of replacing lipid rich in omega-6 fatty acids (corn oil) with lipid-rich in omega-3 fatty acids (fish oil) in the nutrient-deficient diet. LPS-challenged malnourished mice that received dietary fish oil showed decreased expression of inflammatory cytokines and Rankl and reduced osteoclast differentiation and activation in the bone marrow. This work demonstrates that the negative effect of inflammatory challenge on bone marrow is amplified in the malnourished host. Increasing dietary intake of omega-3 fatty acids may be a means to reduce inflammation and improve bone health in malnourished children.