Non-Hematopoietic and Hematopoietic SIRPα Signaling Differently Regulates Murine B Cell Maturation in Bone Marrow and Spleen.
Non-Hematopoietic and Hematopoietic SIRPα Signaling Differently Regulates Murine B Cell Maturation in Bone Marrow and Spleen.
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DOI：
10.1371/journal.pone.0134113
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Oldenborg PA
中科院分区：
文献类型：
--
作者：
Kolan SS;Lejon K;Koskinen Holm C;Sulniute R;Lundberg P;Matozaki T;Oldenborg PA
B淋巴细胞发育发生在骨髓中，而最终的分化和成熟可以发生在骨髓和脾中。在这里，我们提供的证据表明，信号调节蛋白α（SIRPα），免疫球蛋白超家族ITIM受体表达的髓细胞，而不是淋巴样细胞，参与调节B细胞的成熟。成年SIRPα突变小鼠缺乏SIRPα信号传导导致骨髓中B细胞成熟降低，表现为半成熟IgD+IgMhi滤泡II型（F-II）和成熟IgD+IgMlo滤泡I型（F-I）B细胞数量减少以及血液B细胞数量减少。此外，SIRPα信号的缺乏也损害了脾脏中滤泡B细胞的成熟。发现SIRPα突变小鼠的成熟BM或脾B细胞表达更高水平的促凋亡蛋白BIM，并且这些B细胞中的凋亡增加。骨髓重建实验表明，骨髓和血液中B细胞成熟缺陷是由于非造血细胞中SIRPα信号的缺乏，而造血SIRPα信号对脾脏中滤泡B细胞的成熟至关重要。除了我们先前在SIRP α突变小鼠中发现的基质细胞缺陷外，还发现在SIRP α突变小鼠的培养骨髓基质细胞中，核因子-κ B受体激活因子配体（RANKL）的基因表达显著降低。这些数据表明，SIRPα信号传导在非造血细胞和造血细胞中分别对维持B细胞成熟和防止成年小鼠骨髓和脾脏中的细胞凋亡具有新的和相反的贡献。
B lymphocyte development occurs in the bone marrow, while final differentiation and maturation can occur in both the bone marrow and the spleen. Here we provide evidence that signal regulatory protein α (SIRPα), an Ig-superfamily ITIM-receptor expressed by myeloid but not by lymphoid cells, is involved in regulating B cell maturation. Lack of SIRPα signaling in adult SIRPα-mutant mice resulted in a reduced maturation of B cells in the bone marrow, evident by reduced numbers of semi-mature IgD+IgMhi follicular type-II (F-II) and mature IgD+IgMlo follicular type-I (F-I) B cells, as well as reduced blood B cell numbers. In addition, lack of SIRPα signaling also impaired follicular B cell maturation in the spleen. Maturing BM or splenic B cells of SIRPα-mutant mice were found to express higher levels of the pro-apoptotic protein BIM and apoptosis was increased among these B cells. Bone marrow reconstitution experiments revealed that the B cell maturation defect in bone marrow and blood was due to lack of SIRPα signaling in non-hematopoietic cells, while hematopoietic SIRPα signaling was important for follicular B cell maturation in the spleen. Adding on to our previous findings of a stromal cell defect in SIRPα-mutant mice was the finding that gene expression of receptor activator of nuclear factor-ĸB ligand (RANKL) was significantly lower in cultured bone marrow stromal cells of SIRPα mutant mice. These data suggest a novel and opposite contribution of SIRPα signaling within non-hematopoietic and hematopoietic cells, respectively, to maintain B cell maturation and to prevent apoptosis in the bone marrow and spleen of adult mice.