过度的白细胞介素-10 和白细胞介素-18 引发噬血细胞性淋巴组织细胞增生症样过度炎症和增强的骨髓生成。
Excessive IL-10 and IL-18 trigger hemophagocytic lymphohistiocytosis-like hyperinflammation and enhanced myelopoiesis.
机构信息
Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Division of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Immunotherapy Research Center for Hematologic Diseases of Hubei Province, Wuhan, China.
Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Immunotherapy Research Center for Hematologic Diseases of Hubei Province, Wuhan, China.
出版信息
J Allergy Clin Immunol. 2022 Nov;150(5):1154-1167. doi: 10.1016/j.jaci.2022.06.017. Epub 2022 Jul 2.
BACKGROUND
Hyperinflammation is a life-threatening condition associated with various clinical disorders characterized by excessive immune activation and tissue damage. Multiple cytokines promote the development of hyperinflammation; however, the contribution of IL-10 remains unclear despite emerging speculations for a pathological role. Clinical observations from hemophagocytic lymphohistiocytosis (HLH), a prototypical hyperinflammatory disease, suggest that IL-18 and IL-10 may collectively promote the onset of a hyperinflammatory state.
OBJECTIVE
We aimed to investigate the collaborative roles of IL-10 and IL-18 in hyperinflammation.
METHODS
A comprehensive plasma cytokine profile for 87 secondary HLH patients was first depicted and analyzed. We then investigated the systemic and cellular effects of coelevated IL-10 and IL-18 in a transgenic mouse model and cultured macrophages. Single-cell RNA sequencing was performed on the monocytes/macrophages isolated from secondary HLH patients to explore the clinical relevance of IL-10/IL-18-mediated cellular signatures. The therapeutic efficacy of IL-10 blockade was tested in HLH mouse models.
RESULTS
Excessive circulating IL-10 and IL-18 triggered a lethal hyperinflammatory disease recapitulating HLH-like phenotypes in mice, driving peripheral lymphopenia and a striking shift toward enhanced myelopoiesis in the bone marrow. IL-10 and IL-18 polarized cultured macrophages to a distinct proinflammatory state with pronounced expression of myeloid cell-recruiting chemokines. Transcriptional characterization suggested the IL-10/IL-18-mediated cellular features were clinically relevant with HLH, showing enhanced granzyme expression and proteasome activation in macrophages. IL-10 blockade protected against the lethal disease in HLH mouse models.
CONCLUSION
Coelevated IL-10 and IL-18 are sufficient to drive HLH-like hyperinflammatory syndrome, and blocking IL-10 is protective in HLH models.
背景
炎症反应亢进是一种危及生命的病症，与多种临床疾病相关，其特征为过度的免疫激活和组织损伤。多种细胞因子促进炎症反应亢进的发展；然而，尽管人们对其病理性作用提出了一些推测，但 IL-10 的作用仍不明确。噬血细胞性淋巴组织细胞增生症（HLH）是一种典型的炎症反应亢进性疾病，临床观察表明 IL-18 和 IL-10 可能共同促进炎症反应亢进状态的发生。
目的
我们旨在研究 IL-10 和 IL-18 在炎症反应亢进中的协同作用。
方法
首先描绘和分析了 87 例继发性 HLH 患者的综合血浆细胞因子谱。然后，我们在转基因小鼠模型和培养的巨噬细胞中研究了共升高的 IL-10 和 IL-18 的全身和细胞效应。对从继发性 HLH 患者分离的单核细胞/巨噬细胞进行单细胞 RNA 测序，以探讨 IL-10/IL-18 介导的细胞特征的临床相关性。在 HLH 小鼠模型中测试了 IL-10 阻断的治疗效果。
结果
过量的循环 IL-10 和 IL-18 引发了一种致命的炎症反应亢进疾病，在小鼠中重现了 HLH 样表型，导致外周淋巴细胞减少和骨髓中明显增强的髓样细胞生成。IL-10 和 IL-18 将培养的巨噬细胞极化到一个独特的促炎状态，表现出明显的髓样细胞募集趋化因子的表达。转录特征表明，IL-10/IL-18 介导的细胞特征与 HLH 具有临床相关性，在巨噬细胞中显示增强的颗粒酶表达和蛋白酶体激活。IL-10 阻断在 HLH 小鼠模型中可预防致命疾病。
结论
共升高的 IL-10 和 IL-18 足以驱动 HLH 样炎症反应亢进综合征，阻断 IL-10 在 HLH 模型中具有保护作用。
Zotero 插件