Production of IL-18 Binding Protein by Radiosensitive and Radioresistant Cells in CpG-Induced Macrophage Activation Syndrome
Production of IL-18 Binding Protein by Radiosensitive and Radioresistant Cells in CpG-Induced Macrophage Activation Syndrome
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DOI：
10.4049/jimmunol.2000168
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发表时间：
2020-08-15
影响因子：
4.4
通讯作者：
Gabay, Cem
中科院分区：
文献类型：
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作者：
Harel, Mathilde;Girard-Guyonvarc'h, Charlotte;Gabay, Cem
IL-18结合蛋白（IL-18 BP）作为天然存在的IL-18诱饵受体。如果IL-18和IL-18 BP之间的平衡失调，则检测到游离生物活性IL-18的异常水平，例如在具有CpG诱导的巨噬细胞活化综合征的IL-18 bp敲除（KO）小鼠的血清中。为了确定IL-18 bp在体内的细胞来源，我们选择性地耗尽IL-18 bp的表达，无论是在放射敏感性或放射抗性细胞之间的野生型（WT）和IL-18 bp KO小鼠骨髓转移。重复注射CpG后，与WT -> WT嵌合体相比，IL-18 bp KO（供体）-> IL-18 bp KO（受体）嵌合体小鼠表现出更严重的疾病，具有增强的IFN-γ特征和循环游离IL-18水平。有趣的是，KO -> WT和WT -> KO小鼠的表型与WT -> WT小鼠的表型没有差异。与这一发现一致，血清IL-18 bp水平在这三组小鼠中相似。IL-18 bp生产的辐射抗性和辐射敏感性细胞的贡献显着变化，根据检查的器官，与辐射敏感性细胞的主要贡献在脾脏中，而不是在肺中的辐射抗性细胞的主要贡献。最后，IFN-γ阻断消除CpG诱导的IL-18 bp的产生，但不消除组成性IL-18 bp的产生。我们的研究结果表明，循环IL-18 bp是诱导响应IFN-γ在CpG诱导的巨噬细胞活化综合征，并存在于高水平的循环，以防止有害的全身效应的IL-18。
IL-18 binding protein (IL-18BP) acts as a naturally occurring IL-18 decoy receptor. If the balance between IL-18 and IL-18BP is dysregulated, abnormal levels of free bioactive IL-18 are detected, such as in the sera of Il-18bp knockout (KO) mice with CpG-induced macrophage activation syndrome. To determine the cellular sources of Il-18bp in vivo, we selectively depleted Il-18bp expression in either radiosensitive or radioresistant cells using bone marrow transfer between wild-type (WT) and Il-18bp KO mice. Following repeated CpG injections, Il-18bp KO (donor) -> Il-18bp KO (recipient) chimeric mice exhibited more severe disease, with an enhanced Ifn-gamma signature and circulating free Il-18 levels, in comparison with WT -> WT chimeras. Interestingly, the phenotype of KO -> WT and WT -> KO mice did not differ from that of WT -> WT mice. Consistent with this finding, serum Il-18bp levels were similar in these three groups of mice. The contribution of radioresistant and radiosensitive cells to Il-18bp production varied markedly according to the organ examined, with a major contribution of radiosensitive cells in the spleen as opposed to a major contribution of radioresistant cells in the lung. Finally, Ifn-gamma blockade abrogated the CpG-induced but not the constitutive Il-18bp production. Our results demonstrate that circulating Il-18bp is induced in response to Ifn-gamma during CpG-induced macrophage activation syndrome and is present at high levels in the circulation to prevent the deleterious systemic effects of Il-18.