Department of Biomedical Sciences, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104.
Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104.
Proc Natl Acad Sci U S A. 2021 Nov 30;118(48). doi: 10.1073/pnas.2100195118.
Global inactivation of IκB kinase (IKK)-α results in defective lymph node (LN) formation and B cell maturation, and loss of IKK-α-dependent noncanonical NF-κB signaling in stromal organizer and hematopoietic cells is thought to underlie these distinct defects. We previously demonstrated that this pathway is also activated in vascular endothelial cells (ECs). To determine the physiologic function of EC-intrinsic IKK-α, we crossed mice with or mice to ablate IKK-α in ECs. Notably, the compound defects of global IKK-α inactivation were recapitulated in and mice, as both lacked all LNs and mature follicular and marginal zone B cell numbers were markedly reduced. However, as and are expressed in all ECs, including blood forming hemogenic ECs, IKK-α was also absent in hematopoietic cells (HC). To determine if loss of HC-intrinsic IKK-α affected LN development, we generated mice lacking IKK-α in only the hematopoietic compartment. While mature B cell numbers were significantly reduced in mice, LN formation was intact. As lymphatic vessels also arise during development from blood ECs, we generated mice lacking IKK-α in lymphatic ECs (LECs) to determine if IKK-α in lymphatic vessels impacts LN development. Strikingly, while mature B cell numbers were normal, LNs were completely absent in mice. Thus, our findings reveal that IKK-α in distinct EC-derived compartments is uniquely required to promote B cell homeostasis and LN development, and we establish that LEC-intrinsic IKK-α is absolutely essential for LN formation.
全球 IκB 激酶（IKK）-α 的失活导致淋巴结（LN）形成和 B 细胞成熟缺陷，并且认为基质组织者和造血细胞中 IKK-α 依赖性非典型 NF-κB 信号的丧失是这些不同缺陷的基础。我们之前证明，这条途径也在血管内皮细胞（EC）中被激活。为了确定 EC 固有 IKK-α 的生理功能，我们将 小鼠与 或 小鼠杂交，以在 EC 中敲除 IKK-α。值得注意的是，在 和 小鼠中重现了全局 IKK-α 失活的复合缺陷，因为两者都缺乏所有的 LN，并且成熟的滤泡和边缘区 B 细胞数量明显减少。然而，由于 和 在所有 EC 中表达，包括造血的造血内皮细胞，因此造血细胞（HC）中也缺乏 IKK-α。为了确定 HC 固有 IKK-α 的缺失是否影响 LN 发育，我们生成了仅在造血区室中缺失 IKK-α的 小鼠。尽管 小鼠中成熟 B 细胞数量明显减少，但 LN 形成完整。由于淋巴管也在发育过程中从血液 EC 中产生，我们生成了缺乏 LEC 中 IKK-α的 小鼠，以确定淋巴管中的 IKK-α 是否影响 LN 发育。令人惊讶的是，尽管成熟 B 细胞数量正常，但在 小鼠中 LN 完全缺失。因此，我们的研究结果表明，不同 EC 衍生区室中的 IKK-α 独特地需要促进 B 细胞稳态和 LN 发育，并且我们确定了 LEC 固有 IKK-α对于 LN 形成是绝对必要的。
