Pleiotropic effects of extended blockade of CSF1R signaling in adult mice.
Pleiotropic effects of extended blockade of CSF1R signaling in adult mice.
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DOI：
10.1189/jlb.2a0114-006r
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发表时间：
2014-08
影响因子：
5.5
通讯作者：
Hume DA
中科院分区：
文献类型：
--
作者：
Sauter KA;Pridans C;Sehgal A;Tsai YT;Bradford BM;Raza S;Moffat L;Gow DJ;Beard PM;Mabbott NA;Smith LB;Hume DA
长期抗CSF 1 R可预防雌性小鼠的年龄依赖性骨丢失，而不会产生CSF 1 R和CSF 1无效突变的表型后果。我们使用抗CSF 1 R抗体长期治疗来研究CSF 1 R信号传导在成年小鼠中的作用。OP/OP小鼠中CSF 1基因的突变产生许多发育异常。CSF 1 R的突变具有甚至更明显的表型，包括围产期致死性，因为存在第二配体IL-34。这些对发育的影响提供了有限的了解CSF 1 R信号转导在成人体内平衡的功能。处理小鼠的胴体重量和几个器官（脾、肾和肝）的重量降低，但总体体重增加。尽管枯否细胞完全丧失，但对肝脏基因表达没有影响。该治疗消融了OCL，增加了骨密度和骨小梁体积，并防止了雌性小鼠随年龄增长而出现的骨量下降。op/op小鼠具有胰腺β细胞和肠壁中潘氏细胞的缺陷。只有后者是再现的抗体治疗，并与杯状细胞数量增加，但没有变化的绒毛结构。雄性op/op小鼠由于睾酮不足而不育。抗CSF 1 R治疗消融睾丸中的间质巨噬细胞，但对睾酮或LH没有持续影响。结果表明，巨噬细胞和OCL稳态中持续需要CSF 1 R信号，但表明CSF 1和CSF 1 R突变的大多数影响是由于对发育的影响。
Prolonged anti-CSF1R prevents age-dependent bone loss in female mice, without the phenotypic consequences of the CSF1R and CSF1 null mutations. We investigated the role of CSF1R signaling in adult mice using prolonged treatment with anti-CSF1R antibody. Mutation of the CSF1 gene in the op/op mouse produces numerous developmental abnormalities. Mutation of the CSF1R has an even more penetrant phenotype, including perinatal lethality, because of the existence of a second ligand, IL-34. These effects on development provide limited insight into functions of CSF1R signaling in adult homeostasis. The carcass weight and weight of several organs (spleen, kidney, and liver) were reduced in the treated mice, but overall body weight gain was increased. Despite the complete loss of Kupffer cells, there was no effect on liver gene expression. The treatment ablated OCL, increased bone density and trabecular volume, and prevented the decline in bone mass seen in female mice with age. The op/op mouse has a deficiency in pancreatic β cells and in Paneth cells in the gut wall. Only the latter was reproduced by the antibody treatment and was associated with increased goblet cell number but no change in villus architecture. Male op/op mice are infertile as a result of testosterone insufficiency. Anti-CSF1R treatment ablated interstitial macrophages in the testis, but there was no sustained effect on testosterone or LH. The results indicate an ongoing requirement for CSF1R signaling in macrophage and OCL homeostasis but indicate that most effects of CSF1 and CSF1R mutations are due to effects on development.