Department of Immunology and Cell Biology, Graduate School of Medicine and Frontier Biosciences, Osaka University, Osaka, Japan.
World Premier International Research Center Initiative Immunology Frontier Research Center, Osaka University, Osaka, Japan.
J Exp Med. 2021 May 3;218(5). doi: 10.1084/jem.20200817.
The cell-cycle status of hematopoietic stem and progenitor cells (HSPCs) becomes activated following chemotherapy-induced stress, promoting bone marrow (BM) regeneration; however, the underlying molecular mechanism remains elusive. Here we show that BM-resident group 2 innate lymphoid cells (ILC2s) support the recovery of HSPCs from 5-fluorouracil (5-FU)-induced stress by secreting granulocyte-macrophage colony-stimulating factor (GM-CSF). Mechanistically, IL-33 released from chemo-sensitive B cell progenitors activates MyD88-mediated secretion of GM-CSF in ILC2, suggesting the existence of a B cell-ILC2 axis for maintaining hematopoietic homeostasis. GM-CSF knockout mice treated with 5-FU showed severe loss of myeloid lineage cells, causing lethality, which was rescued by transferring BM ILC2s from wild-type mice. Further, the adoptive transfer of ILC2s to 5-FU-treated mice accelerates hematopoietic recovery, while the reduction of ILC2s results in the opposite effect. Thus, ILC2s may function by "sensing" the damaged BM spaces and subsequently support hematopoietic recovery under stress conditions.
造血干细胞和祖细胞（HSPCs）的细胞周期状态在化疗诱导的应激后被激活，促进骨髓（BM）再生；然而，其潜在的分子机制仍不清楚。在这里，我们表明 BM 驻留的 2 型固有淋巴细胞（ILC2）通过分泌粒细胞-巨噬细胞集落刺激因子（GM-CSF）来支持 HSPC 从 5-氟尿嘧啶（5-FU）诱导的应激中恢复。在机制上，来自对化疗敏感的 B 细胞祖细胞的 IL-33 激活了 ILC2 中 MyD88 介导的 GM-CSF 分泌，表明存在 B 细胞-ILC2 轴以维持造血稳态。用 5-FU 处理的 GM-CSF 敲除小鼠表现出严重的髓系细胞丢失，导致死亡，而从野生型小鼠中转移 BM ILC2 则可以挽救。此外，将 ILC2 过继转移到 5-FU 处理的小鼠中可加速造血恢复，而减少 ILC2 则会产生相反的效果。因此，ILC2 可能通过“感知”受损的 BM 空间，并在应激条件下随后支持造血恢复。
