Krefting Research Centre, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Centre for Bone and Arthritis Research, Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Front Immunol. 2022 Jun 3;13:915906. doi: 10.3389/fimmu.2022.915906. eCollection 2022.
The alarmin cytokine interleukin (IL)-33 plays an important proinflammatory role in type 2 immunity and can act on type 2 innate lymphoid cells (ILC2s) and type 2 T helper (T2) cells in eosinophilic inflammation and asthma. The mechanistic target of rapamycin (mTOR) signaling pathway drives immune responses in several inflammatory diseases, but its role in regulating bone marrow responses to IL-33 is unclear. The aim of this study was to determine the role of the mTORC1 signaling pathway in IL-33-induced bone marrow ILC2 responses and its impact on IL-33-induced eosinophilia. Wild-type mice were intranasally exposed to IL-33 only or in combination with the mTORC1 inhibitor, rapamycin, intraperitoneally. Four groups were included in the study: saline-treated (PBS)+PBS, rapamycin+PBS, PBS+IL-33 and rapamycin+IL-33. Bronchoalveolar lavage fluid (BALF), serum and bone marrow cells were collected and analyzed by differential cell count, enzyme-linked immunosorbent assay and flow cytometry. IL-33 induced phosphorylation of the mTORC1 protein rpS6 in bone marrow ILC2s both and . The observed mTOR signal was reduced by rapamycin treatment, indicating the sensitivity of bone marrow ILC2s to mTORC1 inhibition. IL-5 production by ILC2s was reduced in cultures treated with rapamycin before stimulation with IL-33 compared to IL-33 only. Bone marrow and airway eosinophils were reduced in mice given rapamycin before IL-33-exposure compared to mice given IL-33 only. Bone marrow ILC2s responded to IL-33 with increased mTORC1 activity and rapamycin treatment successfully decreased IL-33-induced eosinophilic inflammation, possibly by inhibition of IL-5-producing bone marrow ILC2s. These findings highlight the importance of investigating specific cells and proinflammatory pathways as potential drivers of inflammatory diseases, including asthma.
白细胞介素 (IL)-33 是一种警报素细胞因子，在 2 型免疫中发挥重要的促炎作用，可作用于嗜酸性粒细胞炎症和哮喘中的 2 型固有淋巴样细胞 (ILC2) 和 2 型 T 辅助 (T2) 细胞。雷帕霉素 (mTOR) 信号通路的机械靶标可驱动几种炎症性疾病的免疫反应，但它在调节骨髓对 IL-33 的反应中的作用尚不清楚。本研究旨在确定 mTORC1 信号通路在 IL-33 诱导的骨髓 ILC2 反应中的作用及其对 IL-33 诱导的嗜酸性粒细胞增多的影响。野生型小鼠仅通过鼻腔暴露于 IL-33 或与 mTORC1 抑制剂雷帕霉素联合腹腔内暴露于 IL-33。研究包括 4 组：盐水处理 (PBS)+PBS、雷帕霉素+PBS、PBS+IL-33 和雷帕霉素+IL-33。通过差异细胞计数、酶联免疫吸附测定和流式细胞术收集和分析支气管肺泡灌洗液 (BALF)、血清和骨髓细胞。IL-33 诱导骨髓 ILC2 中 mTORC1 蛋白 rpS6 的磷酸化 和 。雷帕霉素处理降低了观察到的 mTOR 信号，表明骨髓 ILC2 对 mTORC1 抑制的敏感性。与仅用 IL-33 刺激的培养物相比，用雷帕霉素预处理然后用 IL-33 刺激时，ILC2 产生的 IL-5 减少。与仅用 IL-33 处理的小鼠相比，在用 IL-33 暴露前给予雷帕霉素的小鼠中，骨髓和气道嗜酸性粒细胞减少。骨髓 ILC2 对 IL-33 做出反应，mTORC1 活性增加，雷帕霉素治疗成功降低了 IL-33 诱导的嗜酸性粒细胞炎症，可能是通过抑制产生 IL-5 的骨髓 ILC2。这些发现强调了研究特定细胞和促炎途径作为包括哮喘在内的炎症性疾病潜在驱动因素的重要性。
