Center for Immunity, Inflammation and Regenerative Medicine (CIIR), Division of Nephrology, Department of Medicine, University of Virginia, PO Box 800133, Charlottesville, VA, 22903, USA.
Sci Rep. 2019 Mar 1;9(1):3215. doi: 10.1038/s41598-019-39886-9.
Kidney injury, whether due to ischemic insults or chemotherapeutic agents, is exacerbated by inflammation, whereas Tregs are protective. We recently showed that IL-2 and IL-33, especially as a hybrid cytokine (IL233 - bearing IL-2 and IL-33 activities in one molecule), potentiated Tregs and group 2 innate lymphoid cells (ILC2) to prevent renal injury. Recent studies have indicated a reparative function for Tregs and ILC2. Here, using doxorubicin-induced nephrotoxic renal injury model, we investigated whether IL233 administration either before, late or very late after renal injury can restore kidney structure and function. We found that IL233 treatment even 2-weeks post-doxorubicin completely restored kidney function accompanied with an increase Treg and ILC2 in lymphoid and renal compartments, augmented anti-inflammatory cytokines and attenuated proinflammatory cytokine levels. IL233 treated mice had reduced inflammation, kidney injury (Score values - saline: 3.34 ± 0.334; IL233 pre: 0.42 ± 0.162; IL233 24 hrs: 1.34 ± 0.43; IL233 1 week: 1.2 ± 0.41; IL233 2 week: 0.47 ± 0.37; IL233 24 hrs + PC61: 3.5 ± 0.74) and fibrosis in all treatment regimen as compared to saline controls. Importantly, mice treated with IL233 displayed a reparative program in the kidneys, as evidenced by increased expression of genes for renal progenitor-cells and nephron segments. Our findings present the first evidence of an immunoregulatory cytokine, IL233, which could be a potent therapeutic strategy that augments Treg and ILC2 to not only inhibit renal injury, but also promote regeneration.
肾损伤，无论是由缺血性损伤还是化学治疗药物引起的，都会加剧炎症反应，而 Tregs 则具有保护作用。我们最近发现，IL-2 和 IL-33，特别是作为一种杂交细胞因子（IL233-在一个分子中同时具有 IL-2 和 IL-33 的活性），可以增强 Tregs 和 2 型固有淋巴细胞（ILC2），以防止肾损伤。最近的研究表明 Tregs 和 ILC2 具有修复功能。在这里，我们使用多柔比星诱导的肾毒性肾损伤模型，研究了在肾损伤之前、晚期或非常晚期给予 IL233 是否可以恢复肾脏结构和功能。我们发现，即使在多柔比星给药后 2 周给予 IL233 治疗，也能完全恢复肾功能，同时增加淋巴和肾脏部位的 Treg 和 ILC2，增加抗炎细胞因子水平，并降低促炎细胞因子水平。IL233 治疗的小鼠炎症、肾损伤（盐水组：3.34±0.334；IL233 预处理组：0.42±0.162；IL233 24 小时组：1.34±0.43；IL233 1 周组：1.2±0.41；IL233 2 周组：0.47±0.37；IL233 24 小时+PC61 组：3.5±0.74）评分值均降低，纤维化程度也降低。重要的是，与盐水对照组相比，用 IL233 治疗的小鼠在肾脏中表现出修复程序，这表现为肾脏祖细胞和肾单位片段的基因表达增加。我们的研究结果首次提供了证据表明，IL233 作为一种免疫调节细胞因子，可能是一种有效的治疗策略，它可以增强 Treg 和 ILC2，不仅抑制肾损伤，还促进再生。
