Targeting adrenergic receptors to mitigate invariant natural killer T cells-induced acute liver injury.
Targeting adrenergic receptors to mitigate invariant natural killer T cells-induced acute liver injury.
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DOI：
10.1016/j.isci.2023.107947
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发表时间：
2023-10-20
期刊：
影响因子：
5.8
通讯作者：
Keller, Alexandre Castro
中科院分区：
文献类型：
--
作者：
Gonzatti, Michelangelo Bauwelz;Freire, Beatriz Marton;Antunes, Maisa Mota;de Menezes, Gustavo Batista;Talbot, Jhimmy;Peron, Jean Pierre Schatzmann;Basso, Alexandre Salgado;Keller, Alexandre Castro
α-半乳糖神经酰胺（αGC）激活的不变自然杀伤T（iNKT）细胞可增强针对肿瘤的细胞毒性免疫应答。然而，α GC诱导的肝损伤是基于iNKT的免疫治疗的限制因素。虽然肾上腺素能受体刺激是抑制炎症诱导的组织损伤的重要免疫抑制信号，但其对不变的自然杀伤T（iNKT）细胞的抗肿瘤活性的影响仍不清楚。我们使用小鼠模型和药理学工具表明，刺激交感神经系统（SNS）抑制α GC诱导的肝损伤，而不损害iNKT细胞的抗肿瘤功能。从机制上讲，SNS刺激可防止iNKT细胞产生TNF-α和肝实质中中性粒细胞蓄积的附带效应。我们的研究结果表明，肾上腺素能信号的调节可以作为基于α GC的免疫治疗的补充方法，以减轻iNKT诱导的肝损伤，而不影响其抗肿瘤活性。iNKT细胞对肾上腺素能信号传导的抑制作用具有抗性肾上腺素能信号传导减轻iNKT诱导的肝损伤交感神经系统药理学调节减轻iNKT诱导的肝损伤癌症;细胞生物学;免疫系统组分;免疫学
Invariant Natural Killer T (iNKT) cell activation by α-galactosylceramide (αGC) potentiates cytotoxic immune responses against tumors. However, αGC-induced liver injury is a limiting factor for iNKT-based immunotherapy. Although adrenergic receptor stimulation is an important immunosuppressive signal that curbs tissue damage induced by inflammation, its effect on the antitumor activity of invariant Natural Killer T (iNKT) cells remains unclear. We use mouse models and pharmacological tools to show that the stimulation of the sympathetic nervous system (SNS) inhibits αGC-induced liver injury without impairing iNKT cells’ antitumoral functions. Mechanistically, SNS stimulation prevents the collateral effect of TNF-α production by iNKT cells and neutrophil accumulation in hepatic parenchyma. Our results suggest that the modulation of the adrenergic signaling can be a complementary approach to αGC-based immunotherapy to mitigate iNKT-induced liver injury without compromising its antitumoral activity. iNKT cells are resistant to the suppressive effects of adrenergic signaling Adrenergic signaling mitigates iNKT-induced liver injury Sympathetic nervous system pharmacologic modulation mitigates iNKT-induced liver injury Cancer; Cell biology; Components of the immune system; Immunology
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影响因子：
4.7
作者：
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通讯作者：
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影响因子：
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