Acute inflammation primes myeloid effector cells for anti-inflammatory STAT6 signaling.
Acute inflammation primes myeloid effector cells for anti-inflammatory STAT6 signaling.
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急性炎症使骨髓效应细胞启动抗炎 STAT6 信号传导。
DOI：
10.1073/pnas.1312525110
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发表时间：
2013
影响因子：
11.1
通讯作者：
Ravetch,JeffreyV
中科院分区：
文献类型：
--
作者：
Wermeling,Fredrik;Anthony,RobertM;Brombacher,Frank;Ravetch,JeffreyV
抗炎药大剂量静脉注射免疫球蛋白被广泛用于抑制炎症，它依赖于特异性的α-2,6-唾液化糖型IgG Fc来诱导白细胞介素4 （IL-4）和信号转导和转录激活因子6 （STAT6）信号传导。在这里，我们发现IL-4的抗炎活性可以归因于这种细胞因子对髓系效应细胞的直接作用，这取决于它们对IL-4受体α链（IL-4Rα/CD124）的表达。然而，在它们的基础状态下，这些细胞表达低水平的IL-4Rα，与其他细胞群相比，预计不会产生显著的信号传导。这种明显的矛盾可以通过观察来解释，即在炎症期间，由各种刺激（包括自身抗体、佐剂和TLR配体）触发，IL-4Rα在这些细胞上特异性上调，为STAT6信号通路启动。这种调节是由一种可溶性的蛋白酶k敏感因子介导的，这种因子由骨髓来源的非b /非t细胞释放到循环中，这些细胞存在于包括肺和脂肪在内的几个器官中。我们认为这种调节是限制过度炎症和组织损伤的稳态机制的一部分。因此，大剂量静脉注射免疫球蛋白利用了一种内源性反馈回路，这种回路一般与炎症有关，可以进一步靶向治疗目的。
The anti-inflammatory drug high-dose intravenous immunoglobulin, widely used to suppress inflammation, depends on a specific α-2,6-sialylated glycoform of IgG Fc to induce Interleukin 4 (IL-4) and Signal Transducer and Activator of Transcription 6 (STAT6) signaling for its activity. Here we show that anti-inflammatory activities of IL-4 can be attributed to the direct action of this cytokine on myeloid effector cells, depending on their expression of the IL-4 receptor alpha chain (IL-4Rα/CD124). However, in their basal state, these cells express low levels of IL-4Rα and would not be expected to result in significant signaling compared with other cell populations. This apparent paradox can be explained by the observation that during inflammation, triggered by a variety of stimuli (including autoantibodies, adjuvants, and TLR ligands), IL-4Rα is up-regulated specifically on these cells, priming them for STAT6 signaling. The regulation is mediated by a soluble, proteinase K-sensitive factor, released to the circulation by bone marrow-derived, non-B/non-T cells found in several organs, including the lungs, and fat. We propose that this regulation is part of a homeostatic mechanism to limit excessive inflammation and tissue damage. High-dose intravenous immunoglobulin thus exploits an endogenous feedback loop, general to inflammation, that could be further targeted for therapeutic purposes.