Brief Report: Interferon-γ-Mediated Immunopathology Potentiated by Toll-Like Receptor 9 Activation in a Murine Model of Macrophage Activation Syndrome.
Brief Report: Interferon-γ-Mediated Immunopathology Potentiated by Toll-Like Receptor 9 Activation in a Murine Model of Macrophage Activation Syndrome.
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DOI：
10.1002/art.40683
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发表时间：
2019-01
期刊：
影响因子：
--
通讯作者：
Behrens EM
中科院分区：
文献类型：
--
作者：
Weaver LK;Chu N;Behrens EM
巨噬细胞活化综合征（MAS）是一种危及生命的细胞因子风暴综合征，发生在基础风湿病患者中。临床前和临床数据表明，干扰素（IFN）γ在MAS中是致病性的，但IFNγ如何引起疾病仍不清楚。在这篇文章中，我们试图确定IFNγ依赖性信号是否与全身先天免疫应答协同作用，以在MAS小鼠模型中驱动细胞因子风暴。在10天的过程中，用5个剂量的Toll样受体（TLR）9激动剂（CpG1826）、IFNγ或两种刺激的组合处理IFNγ缺陷型小鼠。MAS免疫病理学通过测量血细胞减少、肝炎、肝脾肿大和炎性骨髓生成的诱导进行评估。建立混合骨髓嵌合体以确定TLR9和IFNγR1依赖性信号是否以细胞内源性或细胞外源性方式诱导增强的骨髓生成。当用重复剂量的TLR9激动剂或IFNγ单独处理时，IFNγ缺陷型小鼠不发展MAS的特征。相比之下，用TLR9激动剂和IFNγ处理的IFNγ缺陷型小鼠发生血细胞减少、肝炎和肝脾肿大，再现MAS的主要临床特征。TLR9和IFNγ依赖性信号协同作用以增强骨髓祖细胞功能并诱导体内骨髓生成，这通过细胞外源性机制发生并与疾病的诱导相关。这些数据表明，TLR9驱动的信号增强IFNγ启动小鼠MAS的作用，并提供证据表明炎症诱导的骨髓生成的诱导是一种常见的TLR和IFNγ依赖性途径，可能有助于MAS的发病机制。
Macrophage Activation Syndrome (MAS) is a life-threatening cytokine storm syndrome that occurs in patients with underlying rheumatologic diseases. Preclinical and clinical data suggest that interferon (IFN)γ is pathogenic in MAS, yet how IFNγ causes disease remains unknown. In this manuscript, we sought to determine whether IFNγ-dependent signals synergize with systemic innate immune responses to drive cytokine storm in a murine model of MAS. IFNγ-deficient mice were treated with five doses of a Toll-like receptor (TLR)9 agonist (CpG1826), IFNγ, or a combination of the two stimuli over the course of ten days. MAS immunopathology was assessed by measuring cytopenias, hepatitis, hepatosplenomegaly, and the induction of inflammatory myelopoiesis. Mixed bone marrow chimeras were created to determine if TLR9- and IFNγR1- dependent signals induce enhanced myelopoiesis in a cell-intrinsic or cell-extrinsic manner. IFNγ-deficient mice do not develop features of MAS when treated with repeated doses of a TLR9 agonist or IFNγ individually. In contrast, IFNγ-deficient mice treated with both a TLR9 agonist and IFNγ develop cytopenias, hepatitis, and hepatosplenomegaly reproducing major clinical features of MAS. TLR9- and IFNγ- dependent signals synergize to enhance myeloid progenitor function and induce myelopoiesis in vivo, which occurs through cell-extrinsic mechanisms and correlates with induction of disease. These data demonstrate that TLR9-driven signals potentiate the effects of IFNγ to initiate murine MAS, and provide evidence that induction of inflammation-induced myelopoiesis is a common TLR- and IFNγ- dependent pathway that may contribute to the pathogenesis of MAS.
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影响因子：
30.3
作者：
Burberry A;Zeng MY;Ding L;Wicks I;Inohara N;Morrison SJ;Núñez G
通讯作者：
Núñez G
影响因子：
20.3
作者：
de Bruin, Alexander M.;Libregts, Sten F.;Nolte, Martijn A.
通讯作者：
Nolte, Martijn A.
影响因子：
--
作者：
Canna, Scott W.;Wrobel, Julia;Chu, Niansheng;Kreiger, Portia A.;Paessler, Michele;Behrens, Edward M.
通讯作者：
Behrens, Edward M.
影响因子：
--
作者：
Fall, Ndate;Barnes, Michael;Grom, Alexei A.
通讯作者：
Grom, Alexei A.
影响因子：
30.8
作者：
Graham, RR;Kozyrev, SV;Alarcón-Riquelme, ME
通讯作者：
Alarcón-Riquelme, ME