造血细胞中 IκBζ 的条件性缺失可促进小鼠脊髓损伤后的功能恢复。

IF 1.5 4区医学 Q3 ORTHOPEDICS

Journal of Orthopaedic Science Pub Date : 2025-03-01 DOI:10.1016/j.jos.2024.04.008

Naoya Taki , Atsushi Kimura , Yasuyuki Shiraishi , Takashi Maruyama , Tsukasa Ohmori , Katsushi Takeshita

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引用次数: 0

摘要

背景：转录因子蛋白 IκBζ（由 Nfkbiz 基因编码）调节核因子-κB（NF-κB），并参与各种炎症性疾病的病理生理学。然而，IκBζ在脊髓损伤（SCI）后继发性损伤中的作用仍有待确定。在此，我们研究了造血细胞中表达的 IκBζ 对脊髓损伤后继发性损伤进展和功能恢复的影响：方法：我们使用条件性 IκBζ 基因敲除小鼠（Mx1-Cre;Nfkbizfl/f）来研究 IκBζ 在 SCI 后造血细胞中的作用。用 60 kdyn 的力诱导挫伤性 SCI。使用九点巴索小鼠量表（BMS）评估运动能力的恢复情况，直至伤后42天。炎症细胞因子和趋化因子的表达模式通过实时定量 PCR 或蛋白质组阵列分析进行了检测。为了消除非造血细胞中IκBζ缺失的影响，进行了骨髓移植（BMT）：结果：与野生型小鼠相比，Mx1-Cre;Nfkbizfl/fl小鼠的运动功能明显改善。WT小鼠的Nfkbiz mRNA表达量在脊髓损伤后12小时达到峰值，随后在脊髓和白细胞中缓慢下降。原位杂交显示，Nfkbiz mRNA定位于脊髓损伤后1天WT小鼠损伤脊髓的细胞核中，包括巨噬细胞样细胞。与WT小鼠相比，Mx1-Cre;Nfkbizfl/fl小鼠损伤脊髓中白细胞介素（Il）-4和Il-10的mRNA表达量明显增加。此外，与 WT 小鼠相比，Mx1-Cre;Nfkbizfl/fl 小鼠的粒细胞-巨噬细胞集落刺激因子和 C-C motif 趋化因子 11 蛋白水平明显更高。将Mx1-Cre;Nfkbizfl/fl小鼠移植到WT小鼠体内，与对照组小鼠（WT细胞移植到WT小鼠体内）相比，可改善SCI后的功能恢复：结论：造血细胞中IκBζ的缺失可改善脊髓损伤后的功能恢复，可能是通过将炎症平衡转向抗炎和促进再生的方向。

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Conditional deletion of IκBζ in hematopoietic cells promotes functional recovery after spinal cord injury in mice

Background

Transcription factor protein IκBζ (encoded by the Nfkbiz gene) regulates nuclear factor-κB (NF-κB) and is involved in the pathophysiology of various inflammatory diseases. However, the role of IκBζ in secondary damage following spinal cord injury (SCI) remains to be determined. Here, we investigated the effect of IκBζ expressed in hematopoietic cells on the progression of secondary damage and functional recovery after SCI.

Methods

We used conditional IκBζ-knockout mice (Mx1-Cre;Nfkbiz^fl/f) to examine the role of IκBζ in hematopoietic cells after SCI. Contusion SCI was induced using a force of 60 kdyn. The recovery of locomotor performance was evaluated using the nine-point Basso Mouse Scale (BMS) until 42 days post-injury. Expression patterns of inflammatory cytokines and chemokines were examined by quantitative real-time PCR or proteome array analysis. Bone marrow transplantation (BMT) was performed to eliminate the effect of IκBζ deletion in non-hematopoietic cells.

Results

Mx1-Cre;Nfkbiz^fl/fl mice had significantly improved locomotor function compared with wild-type (WT) mice. The mRNA expression of Nfkbiz in WT mice peaked at 12 h after SCI and then decreased slowly in both the spinal cord and white blood cells. In situ hybridization showed that Nfkbiz mRNA was localized in cell nuclei, including macrophage-like cells, in the injured spinal cord of WT mice at 1 day after SCI. Compared with WT mice, Mx1-Cre;Nfkbiz^fl/fl mice had significantly increased mRNA expressions of interleukin (Il)-4 and Il-10 in the injured spinal cord. In addition, Mx1-Cre;Nfkbiz^fl/fl mice had significantly higher protein levels of granulocyte-macrophage colony-stimulating factor and C–C motif chemokine 11 compared with WT mice. BMT from Mx1-Cre;Nfkbiz^fl/fl mice into WT mice improved functional recovery after SCI compared with control mice (WT cells into WT mice).

Conclusions

IκBζ deletion in hematopoietic cells improved functional recovery after SCI, possibly by shifting the inflammatory balance towards anti-inflammatory and pro-regenerative directions.

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来源期刊

Journal of Orthopaedic Science 医学-整形外科

CiteScore

3.00

自引率

0.00%

发文量

290

审稿时长

90 days

期刊介绍： The Journal of Orthopaedic Science is the official peer-reviewed journal of the Japanese Orthopaedic Association. The journal publishes the latest researches and topical debates in all fields of clinical and experimental orthopaedics, including musculoskeletal medicine, sports medicine, locomotive syndrome, trauma, paediatrics, oncology and biomaterials, as well as basic researches.