Lobo-Silva Diogo, Carriche Guilhermina M, Castro A Gil, Roque Susana, Saraiva Margarida
Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal.
ICVS/3B's PT Government Associate Laboratory, Braga/Guimarães, Portugal.
Glia. 2017 Sep;65(9):1439-1451. doi: 10.1002/glia.23172. Epub 2017 Jun 15.
Pattern recognition receptors, such as toll-like receptors (TLRs), perceive tissue alterations and initiate local innate immune responses. Microglia, the resident macrophages of the brain, encode TLRs which primary role is to protect the tissue integrity. However, deregulated activation of TLRs in microglia may lead to chronic neurodegeneration. This double role of microglial responses is often reported in immune-driven neurologic diseases, as in multiple sclerosis (MS). Consequently, strategies to manipulate microglia inflammatory responses may help to ameliorate disease progression. In this context, the anti-inflammatory cytokine interleukin (IL)-10 appears as an attractive target. In this study, we investigated how activation of microglia by TLRs with distinct roles in MS impacts on IL-10 production. We found that activation of TLR2, TLR4, and TLR9 induced the production of IL-10 to a greater extent than activation of TLR3. This was surprising as both TLR3 and IL-10 play protective roles in animal models of MS. Interestingly, combination of TLR3 triggering with the other TLRs, enhanced IL-10 through the modulation of its transcription, via interferon (IFN)-β, but independently of IL-27. Thus, in addition to the modulation of inflammatory responses of the periphery described for the axis TLR3/IFN-β, we now report a direct modulation of microglial responses. We further show that the presence of IFN-γ in the microenvironment abrogated the modulation of IL-10 by TLR3, whereas that of IL-17 had no effect. Considering the therapeutic application of IFN-β in MS, our study bears important implications for the understanding of the cytokine network regulating microglia responses in this setting.
模式识别受体，如Toll样受体（TLR），可感知组织变化并启动局部先天性免疫反应。小胶质细胞是大脑中的常驻巨噬细胞，编码TLR，其主要作用是保护组织完整性。然而，小胶质细胞中TLR的失调激活可能导致慢性神经退行性变。小胶质细胞反应的这种双重作用在免疫驱动的神经系统疾病中经常被报道，如在多发性硬化症（MS）中。因此，操纵小胶质细胞炎症反应的策略可能有助于改善疾病进展。在这种情况下，抗炎细胞因子白细胞介素（IL）-10似乎是一个有吸引力的靶点。在本研究中，我们研究了在MS中具有不同作用的TLR激活小胶质细胞如何影响IL-10的产生。我们发现，与TLR3激活相比，TLR2、TLR4和TLR9的激活在更大程度上诱导了IL-10的产生。这令人惊讶，因为TLR3和IL-10在MS动物模型中都发挥保护作用。有趣的是，TLR3触发与其他TLR的组合，通过干扰素（IFN）-β调节IL-10的转录，增强了IL-10的产生，但与IL-27无关。因此，除了TLR3/IFN-β轴对外周炎症反应的调节外，我们现在报道了对小胶质细胞反应的直接调节。我们进一步表明，微环境中IFN-γ的存在消除了TLR3对IL-10的调节，而IL-17的存在则没有影响。考虑到IFN-β在MS中的治疗应用，我们的研究对理解在这种情况下调节小胶质细胞反应的细胞因子网络具有重要意义。
