内源性神经调节蛋白-4 的缺失限制了白细胞介素-10 受体中和性结肠炎期间的适应性免疫。
Deletion of Endogenous Neuregulin-4 Limits Adaptive Immunity During Interleukin-10 Receptor-Neutralizing Colitis.
机构信息
Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA, USA.
Craniofacial Biology Program, Herman Ostrow School of Dentistry, University of Southern California, Los Angeles, CA, USA.
出版信息
Inflamm Bowel Dis. 2023 Nov 2;29(11):1778-1792. doi: 10.1093/ibd/izad092.
BACKGROUND
Growth factors are essential for maintenance of intestinal health. We previously showed that exogenous neuregulin-4 (NRG4) promotes colonocyte survival during cytokine challenge and is protective against acute models of intestinal inflammation. However, the function(s) of endogenous NRG4 are not well understood. Using NRG4-/- mice, we tested the role of endogenous NRG4 in models of colitis skewed toward either adaptive (interleukin-10 receptor [IL-10R] neutralization) or innate (dextran sulfate sodium [DSS]) immune responses.
METHODS
NRG4-/- and wild-type cage mate mice were subjected to chronic IL-10R neutralization colitis and acute DSS colitis. Disease was assessed by histological examination, inflammatory cytokine levels, fecal lipocalin-2 levels, and single cell mass cytometry immune cell profiling. Homeostatic gene alterations were evaluated by RNA sequencing analysis from colonic homogenates, with real-time quantitative polymerase chain reaction confirmation in both tissue and isolated epithelium.
RESULTS
During IL-10R neutralization colitis, NRG4-/- mice had reduced colonic inflammatory cytokine expression, histological damage, and colonic CD8+ T cell numbers vs wild-type cage mates. Conversely, in DSS colitis, NRG4-/- mice had elevated cytokine expression, fecal lipocalin-2 levels, and impaired weight recovery. RNA sequencing showed a loss of St3gal4, a sialyltransferase involved in immune cell trafficking, in NRG4-null colons, which was verified in both tissue and isolated epithelium. The regulation of St3gal4 by NRG4 was confirmed with ex vivo epithelial colon organoid cultures from NRG4-/- mice and by induction of St3gal4 in vivo following NRG4 treatment.
CONCLUSIONS
NRG4 regulates colonic epithelial ST3GAL4 and thus may allow for robust recruitment of CD8+ T cells during adaptive immune responses in colitis. On the other hand, NRG4 loss exacerbates injury driven by innate immune responses.
背景
生长因子对于维持肠道健康至关重要。我们之前的研究表明，外源性神经调节蛋白 4（NRG4）可促进细胞因子刺激下的结肠细胞存活，并对急性肠道炎症模型具有保护作用。然而，内源性 NRG4 的功能尚不清楚。本研究利用 NRG4-/- 小鼠，在偏向适应性（白细胞介素 10 受体[IL-10R]中和）或固有（葡聚糖硫酸钠[DSS]）免疫反应的结肠炎模型中，检测内源性 NRG4 的作用。
方法
NRG4-/-和野生型同笼小鼠分别接受慢性 IL-10R 中和结肠炎和急性 DSS 结肠炎。通过组织学检查、炎症细胞因子水平、粪便脂联素-2 水平和单细胞质量细胞术免疫细胞分析来评估疾病。利用结肠匀浆的 RNA 测序分析评估稳态基因改变，并在组织和分离的上皮组织中进行实时定量聚合酶链反应验证。
结果
在 IL-10R 中和结肠炎中，与野生型同笼小鼠相比，NRG4-/- 小鼠的结肠炎症细胞因子表达、组织损伤和 CD8+T 细胞数量减少。相反，在 DSS 结肠炎中，NRG4-/- 小鼠的细胞因子表达、粪便脂联素-2 水平升高，体重恢复受损。RNA 测序显示，NRG4 缺失的结肠中一种参与免疫细胞迁移的唾液酸转移酶 St3gal4 丢失，在组织和分离的上皮组织中均得到验证。通过 NRG4-/- 小鼠的上皮结肠类器官培养物进行的体外实验和 NRG4 处理后体内诱导 St3gal4 的实验，证实了 NRG4 对 St3gal4 的调控。
结论
NRG4 调节结肠上皮 ST3GAL4，从而可能在结肠炎适应性免疫反应中允许 CD8+T 细胞的大量募集。另一方面，NRG4 的缺失加剧了固有免疫反应引起的损伤。
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