IL4 induces IL6-producing M2 macrophages associated to inhibition of neuroinflammation in vitro and in vivo.
IL4 induces IL6-producing M2 macrophages associated to inhibition of neuroinflammation in vitro and in vivo.
复制标题
IL4诱导与抑制神经炎症的体外和体内抑制有关的产生IL6的M2巨噬细胞。
DOI：
10.1186/s12974-016-0596-5
复制
发表时间：
2016-06-07
影响因子：
9.3
通讯作者：
Furlan R
中科院分区：
文献类型：
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作者：
Casella G;Garzetti L;Gatta AT;Finardi A;Maiorino C;Ruffini F;Martino G;Muzio L;Furlan R
骨髓细胞，如巨噬细胞和小胶质细胞，在神经炎症中起着至关重要的作用，最近已被确定为一种新的治疗靶点，特别是对于慢性形式。总体目标是将髓样细胞的表型从促炎性改变为抗炎性，有利于其组织营养和再生功能。然而，髓样细胞显示出许多功能表型，不能立即识别为促炎或抗炎，并且与模糊的标记物相关。我们采用体外测定来研究在经典极化刺激如IFN γ（促炎）和IL 4（抗炎）存在下巨噬细胞极化/分化。我们通过用髓鞘抗原免疫小鼠诱导神经炎症，并用脑池内递送表达IL 4的慢病毒载体治疗患病小鼠。我们分析了临床、病理和免疫学结果，重点是骨髓细胞。我们发现，IL 6，通常被认为是一种促炎细胞因子，在体外释放的巨噬细胞与抗炎细胞因子IL 4处理。我们显示存在表达IL 6的巨噬细胞沿着经典的抗炎标志物如CD 206，并证明这些细胞在体外具有免疫抑制作用。在神经发炎的小鼠中，我们表明IL 4在中枢神经系统（CNS）中的递送与疾病的临床和病理保护相关，与浸润性巨噬细胞中IL 6表达增加相关。已知IL 6介导促炎和抗炎作用，具有两种不同的方式来诱导细胞信号传导：通过膜结合受体（抗炎）或通过反式信号传导（促炎）。我们在这里表明，IL-6表达巨噬细胞与神经炎症的保护，这表明IL-6抗炎特性在中枢神经系统中占主导地位，并呼吁对IL-6在巨噬细胞极化的一般重新考虑。本文的在线版本（doi：10.1186/s12974 - 016 - 0596 - 5）包含补充材料，可供授权用户使用。
Myeloid cells, such as macrophages and microglia, play a crucial role in neuroinflammation and have been recently identified as a novel therapeutic target, especially for chronic forms. The general aim would be to change the phenotype of myeloid cells from pro- to anti-inflammatory, favoring their tissue-trophic and regenerative functions. Myeloid cells, however, display a number of functional phenotypes, not immediately identifiable as pro- or anti-inflammatory, and associated to ambiguous markers. We employed in vitro assays to study macrophage polarization/differentiation in the presence of classical polarizing stimuli such as IFNγ (pro-inflammatory) and IL4 (anti-inflammatory). We induced neuroinflammation in mice by immunization with a myelin antigen and treated diseased mice with intracisternal delivery of an IL4-expressing lentiviral vector. We analyzed clinical, pathological, and immunological outcomes with a focus on myeloid cells. We found that IL6, usually considered a pro-inflammatory cytokine, was released in vitro by macrophages treated with the anti-inflammatory cytokine IL4. We show the existence of macrophages expressing IL6 along with classical anti-inflammatory markers such as CD206 and demonstrate that these cells are immunosuppressive in vitro. In neuroinflamed mice, we show that IL4 delivery in the central nervous system (CNS) is associated with clinical and pathological protection from disease, associated with increased IL6 expression in infiltrating macrophages. IL6 is known to mediate both pro- and anti-inflammatory effects, having two distinct ways to induce cell-signaling: either through the membrane bound receptor (anti-inflammatory) or through trans-signaling (pro-inflammatory). We show here that IL6-expressing macrophages are associated to protection from neuroinflammation, suggesting that IL6 anti-inflammatory properties prevail in the CNS, and calling for a general reconsideration of IL6 in macrophage polarization. The online version of this article (doi:10.1186/s12974-016-0596-5) contains supplementary material, which is available to authorized users.