Age-related exacerbation of hematopoietic organ damage induced by systemic hyper-inflammation in senescence-accelerated mice.
Age-related exacerbation of hematopoietic organ damage induced by systemic hyper-inflammation in senescence-accelerated mice.
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DOI：
10.1038/s41598-021-02621-4
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发表时间：
2021-12-01
影响因子：
4.6
通讯作者：
Aizawa S
中科院分区：
文献类型：
--
作者：
Harada T;Tsuboi I;Hino H;Yuda M;Hirabayashi Y;Hirai S;Aizawa S
噬血细胞性淋巴组织细胞增多症（HLH）是一种危及生命的全身性高炎症性疾病。HLH在老年人中的死亡率高于年轻人。衰老加速小鼠（SAMP1/TA-1）在30周龄后表现出特征性的加速衰老，脂多糖（LPS）处理后出现hlh样特征，包括造血器官损伤。因此，SAMP1/TA-1是老年HLH患者血液病理生理的一个有用模型。在本研究中，给SAMP1/TA-1小鼠注射LPS，发现老年小鼠的骨髓生成和b淋巴生成受到的抑制比年轻小鼠更严重。两组小鼠骨髓中编码骨髓生成阳性调节因子（G-CSF、GM-CSF和IL-6）和编码B细胞淋巴生成阴性调节因子（TNF-α）的基因表达均升高，而编码B细胞淋巴生成阳性调节因子（IL-7、SDF-1和SCF）的基因表达则降低。老龄小鼠中gm - csf编码转录物的表达低于幼龄小鼠。衰老小鼠经LPS处理后基质细胞产生的GM-CSF也低于年轻小鼠。与幼龄小鼠相比，老龄小鼠TNF-α-编码转录物的积累和il -7编码转录物的消耗被延长。与年轻动物相比，LPS剂量导致老年小鼠BM M1巨噬细胞比例的延长。老龄小鼠基质细胞中编码p16INK4a基因的表达以及β-半乳糖苷酶和磷酸化核糖体蛋白s6阳性细胞的比例均高于幼龄小鼠，而ki67阳性细胞的比例则低于幼龄小鼠。因此，与年龄相关的基质细胞退化可能导致老年小鼠造血功能的抑制。这种与年龄相关的潜在器官功能障碍可能在老年HLH患者中加剧，导致预后不良。
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening systemic hyper-inflammatory disorder. The mortality of HLH is higher in the elderly than in young adults. Senescence-accelerated mice (SAMP1/TA-1) exhibit characteristic accelerated aging after 30 weeks of age, and HLH-like features, including hematopoietic organ damage, are seen after lipopolysaccharide (LPS) treatment. Thus, SAMP1/TA-1 is a useful model of hematological pathophysiology in the elderly with HLH. In this study, dosing of SAMP1/TA-1 mice with LPS revealed that the suppression of myelopoiesis and B-lymphopoiesis was more severe in aged mice than in young mice. The bone marrow (BM) expression of genes encoding positive regulators of myelopoiesis (G-CSF, GM-CSF, and IL-6) and of those encoding negative regulators of B cell lymphopoiesis (TNF-α) increased in both groups, while the expression of genes encoding positive-regulators of B cell lymphopoiesis (IL-7, SDF-1, and SCF) decreased. The expression of the GM-CSF-encoding transcript was lower in aged mice than in young animals. The production of GM-CSF by cultured stromal cells after LPS treatment was also lower in aged mice than in young mice. The accumulation of the TNF-α-encoding transcript and the depletion of the IL-7-encoding transcript were prolonged in aged mice compared to young animals. LPS dosing led to a prolonged increase in the proportion of BM M1 macrophages in aged mice compared to young animals. The expression of the gene encoding p16INK4a and the proportion of β-galactosidase- and phosphorylated ribosomal protein S6-positive cells were increased in cultured stromal cells from aged mice compared to those from young animals, while the proportion of Ki67-positive cells was decreased in stromal cells from aged mice. Thus, age-related deterioration of stromal cells probably causes the suppression of hematopoiesis in aged mice. This age-related latent organ dysfunction may be exacerbated in elderly people with HLH, resulting in poor prognosis.
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影响因子：
3.2
作者：
Tsuboi, I;Morimoto, K;Inoue, T
通讯作者：
Inoue, T
影响因子：
56.9
作者：
Stepp, SE;Dufourcq-Lagelouse, R;Kumar, V
通讯作者：
Kumar, V
影响因子：
4.4
作者：
Boettcher, Steffen;Ziegler, Patrick;Manz, Markus G.
通讯作者：
Manz, Markus G.
影响因子：
2
作者：
Taki, Masafumi;Tsuboi, Isao;Aizawa, Shin
通讯作者：
Aizawa, Shin
影响因子：
5.6
作者：
Alessio N;Aprile D;Cappabianca S;Peluso G;Di Bernardo G;Galderisi U
通讯作者：
Galderisi U