IFN-γ Prevents Adenosine Receptor (A2bR) Upregulation To Sustain the Macrophage Activation Response.
IFN-γ Prevents Adenosine Receptor (A2bR) Upregulation To Sustain the Macrophage Activation Response.
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DOI：
10.4049/jimmunol.1501139
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发表时间：
2015-10-15
期刊：
影响因子：
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通讯作者：
Mosser DM
中科院分区：
文献类型：
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作者：
Cohen HB;Ward A;Hamidzadeh K;Ravid K;Mosser DM
在TLR刺激之前用IFN-γ引发巨噬细胞导致增强和延长的炎性细胞因子产生。在这里，我们证明了TLR刺激后，巨噬细胞上调腺苷2b受体（A2 bR），以增强其对免疫抑制性细胞外腺苷的敏感性。A2 bR的这种上调导致具有免疫调节表型的巨噬细胞的诱导和炎症的下调。巨噬细胞的IFN-γ引发选择性地阻止巨噬细胞中A2 bR的诱导，以减轻对腺苷的敏感性并阻止这种调节转变。IFN-γ介导的A2 bR阻断导致响应TLR连接的TNFα和IL-12的产生延长。A2 bR的药理学抑制或遗传缺失导致对TLR连接的高度炎症反应，类似于巨噬细胞的IFN-γ处理。相反，A2 bR在巨噬细胞上的过表达减弱了IFN-γ的作用并促进免疫调节性巨噬细胞的发育。因此，我们提出了一种新的机制，IFN-γ有助于宿主防御，脱敏巨噬细胞的免疫调节作用的腺苷。这种机制克服了TLR活化的瞬时性质，并抑制了经典活化的巨噬细胞的抗微生物状态。这项研究可能提供有前途的新靶点，以改善炎症性疾病的临床结果，其中巨噬细胞活化失调。
The priming of macrophages with IFN-γ prior to TLR stimulation results in enhanced and prolonged inflammatory cytokine production. Here, we demonstrate that following TLR stimulation, macrophages up regulate the adenosine 2b receptor (A2bR) to enhance their sensitivity to immunosuppressive extracellular adenosine. This up-regulation of A2bR leads to the induction of a macrophage with an immunoregulatory phenotype and the down regulation of inflammation. IFN-γ priming of macrophages, selectively prevents the induction of the A2bR in macrophages to mitigate sensitivity to adenosine and prevent this regulatory transition. IFN-γ-mediated A2bR blockade leads to a prolonged production of TNFα and IL-12 in response to TLR ligation. The pharmacological inhibition or the genetic deletion of the A2bR results in a hyper-inflammatory response to TLR ligation, similar to IFN-γ treatment of macrophages. Conversely, the overexpression of A2bR on macrophages blunts the IFN-γ effects and promotes the development of immunoregulatory macrophages. Thus, we propose a novel mechanism whereby IFN-γ contributes to host defense, by desensitizing macrophages to the immunoregulatory effects of adenosine. This mechanism overcomes the transient nature of TLR activation, and prolongs the anti-microbial state of the classically activated macrophage. This study may offer promising new targets to improve the clinical outcome of inflammatory diseases in which macrophage activation is dysregulated.