Constitutive alternative NF-κB signaling promotes marginal zone B-cell development but disrupts the marginal sinus and induces HEV-like structures in the spleen
Constitutive alternative NF-κB signaling promotes marginal zone B-cell development but disrupts the marginal sinus and induces HEV-like structures in the spleen
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DOI：
10.1182/blood-2007-02-075143
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发表时间：
2007-10-01
期刊：
影响因子：
20.3
通讯作者：
Weih, Falk
中科院分区：
文献类型：
--
作者：
Guo, Feng;Weih, Debra;Weih, Falk
核因子κ B （nf - κ B）在B细胞和淋巴器官的发育中起着至关重要的作用。在这里，我们研究了脾边缘区（MZ）的nf - κ B替代通路的组成性、信号独立激活的后果。与缺乏p100和p52的nfkb2（-/-）小鼠相反，仅缺乏抑制p100前体但仍表达NF-kappa B2的p52亚基（p100(-/-)）的小鼠MZ b细胞数量明显升高。细胞内在机制和血管细胞粘附分子-1 （VCAM-1）在基质中的表达增加都有助于p100（-/-）脾脏中MZ B细胞的积累。虽然p100(-/-) MZ B细胞向溶血磷脂鞘鞘醇-1磷酸（S1P）的迁移不受影响，但cxcl13刺激的趋化性受损，这与MZ B细胞响应脂多糖（LPS）向卵泡迁移的减少有关。引人注目的是，p100缺乏导致正常边缘窦的缺失，强烈诱导粘膜定位蛋白细胞粘附分子-1 （MAdCAM-1）和糖基化细胞粘附分子-1 （GlyCAM1）的表达，并在红髓中形成无功能异位高内皮小静脉（HEV）样结构。因此，nf - κ B通路的组成性激活有利于MZ B细胞的发育和积累，但会导致脾脏微结构紊乱。
Nuclear factor-kappa B (NF-kappa B) plays a crucial role in B-cell and lymphoid organ development. Here, we studied the consequences of constitutive, signal-independent activation of the alternative NF-kappa B pathway for the splenic marginal zone (MZ). In contrast to nfkb2(-/-) mice, which lack both p100 and p52, mice that lack only the inhibitory p100 precursor but still express the p52 subunit of NF-kappa B2 (p100(-/-)) had markedly elevated MZ B-cell numbers. Both cell-intrinsic mechanisms and increased stromal expression of vascular cell adhesion molecule-1 (VCAM-1) contributed to the accumulation of MZ B cells in p100(-/-) spleens. While migration of p100(-/-) MZ B cells toward the lysophospholipid sphingosine-1 phosphate (S1P) was not affected, CXCL13-stimulated chemotaxis was impaired, correlating with reduced migration of MZ B cells into follicles in response to lipopolysaccharide (LPS). Strikingly, p100 deficiency resulted in the absence of a normal marginal sinus, strongly induced expression of mucosal addressin cell adhesion molecule-1 (MAdCAM-1) and glycosylated cell adhesion molecule-1 (GlyCAM1), and the formation of nonfunctional ectopic high endothelial venule (HEV)-like structures in the red pulp. Thus, constitutive activation of the alternative NF-kappa B pathway favors MZ B-cell development and accumulation but leads to a disorganized spleen microarchitecture.