Irgm1 is required for the inflammatory function of M1 macrophage in early experimental autoimmune encephalomyelitis
Irgm1 is required for the inflammatory function of M1 macrophage in early experimental autoimmune encephalomyelitis
复制标题
早期实验性自身免疫性脑脊髓炎中 M1 巨噬细胞的炎症功能需要 Irgm1
DOI：
10.1189/jlb.3a0116-028rr
复制
发表时间：
2017-02-01
影响因子：
5.5
通讯作者：
Sun，Bo
中科院分区：
文献类型：
--
作者：
Xu，Yanwen;He，Zhongze;Sun，Bo
经典活化（M1）巨噬细胞已被证明在实验性自身免疫性脑脊髓炎（EAE）（多发性硬化症（MS）的动物模型）中发挥不可或缺的作用。然而，大多数研究集中在巨噬细胞对EAE中枢神经系统脱髓鞘的影响；M1巨噬细胞是否参与早期EAE及其分子机制尚不清楚。在这里，我们发现免疫相关的GTPase家族成员1 (Irgm1)，也被称为LRG‐47，在早期EAE的C57BL/6小鼠的引流淋巴结（dln）的M1巨噬细胞中表达，Irgm1杂合子显著减少了原发性EAE阶段dln和脾脏中的M1巨噬细胞积累。在M1巨噬细胞中，IRGM1的体外沉默会损害NOS2的表达和炎症细胞因子的释放。我们还发现IRGM1敲除M1巨噬细胞（IRGM1−/−）增加了Akt的激活，但减弱了NF - κB p65的激活，这可能揭示了IRGM1介导的作用机制。有趣的是，体内巨噬细胞耗竭抑制了脾脏中Th1/Th17的分化，并在刺激后7天（dpi）时促进了dln中的调节性T细胞（Treg）极化。此外，我们在体外观察到M1巨噬细胞促进Th1/Th17分化，而IRGM1小干扰RNA （siRNA）、抗TNF - α或抗IL - 1β单抗可逆转这一分化。这些结果提示，在EAE早期，M1巨噬细胞可能促进Th1/Th17细胞的分化，M1细胞的促炎功能需要Irgm1。
The classically activated (M1) macrophage has been shown to play an indispensable role in experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS). However, most studies focus on the effect of macrophage on CNS demyelination of EAE; whether the M1 macrophage participates in early EAE and the molecular mechanism underlying remains unclear. Here, we showed that the immunity‐related GTPase family member 1 (Irgm1), also known as LRG‐47, was expressed in M1 macrophages of draining lymph nodes (dLNs) from C57BL/6 mice with early EAE, and the IRGM1 heterozygote substantially reduced M1 macrophage accumulation in dLNs and spleen of the primary EAE stage. In vitro silence of IRGM1 in M1 macrophages impaired NOS2 expression and inflammatory cytokine release. We also found that IRGM1 knockout (Irgm1−/−) in M1 macrophages increased Akt activation but attenuated NF‐κB p65 activation, which may reveal Irgm1‐mediated mechanisms of action. Interestingly, macrophage depletion in vivo inhibited Th1/Th17 differentiation in the spleen and promoted regulatory T cell (Treg) polarization in dLNs at 7 d postimmunization (dpi). Moreover, we observed that M1 macrophages in vitro promoted Th1/Th17 differentiation, which was reversed by treatment with IRGM1 small interfering RNA (siRNA), anti‐TNF‐α, or anti‐IL‐1β mAb. These results suggest that the M1 macrophage may promote Th1/Th17 cell differentiation during the early EAE, and the proinflammatory function of M1 cells requires Irgm1.