Division of Immunology, Tulane National Primate Research Center, Tulane University, 18703, Three Rivers Road, Room 109, Covington, LA, 70433, USA.
Division of Microbiology, Tulane National Primate Research Center, Tulane University, 18703, Three Rivers Road, Covington, LA, 70433, USA.
J Neuroinflammation. 2023 Jan 17;20(1):10. doi: 10.1186/s12974-022-02681-x.
Lyme neuroborreliosis, caused by the bacterium Borrelia burgdorferi affects both the central and peripheral nervous systems (CNS, PNS). The CNS manifestations, especially at later stages, can mimic/cause many other neurological conditions including psychiatric disorders, dementia, and others, with a likely neuroinflammatory basis. The pathogenic mechanisms associated with Lyme neuroborreliosis, however, are not fully understood.
In this study, using cultures of primary rhesus microglia, we explored the roles of several fibroblast growth factor receptors (FGFRs) and fibroblast growth factors (FGFs) in neuroinflammation associated with live B. burgdorferi exposure. FGFR specific siRNA and inhibitors, custom antibody arrays, ELISAs, immunofluorescence and microscopy were used to comprehensively analyze the roles of these molecules in microglial neuroinflammation due to B. burgdorferi.
FGFR1-3 expressions were upregulated in microglia in response to B. burgdorferi. Inhibition of FGFR 1, 2 and 3 signaling using siRNA and three different inhibitors showed that FGFR signaling is proinflammatory in response to the Lyme disease bacterium. FGFR1 activation also contributed to non-viable B. burgdorferi mediated neuroinflammation. Analysis of the B. burgdorferi conditioned microglial medium by a custom antibody array showed that several FGFs are induced by the live bacterium including FGF6, FGF10 and FGF12, which in turn induce IL-6 and/or CXCL8, indicating a proinflammatory nature. To our knowledge, this is also the first-ever described role for FGF6 and FGF12 in CNS neuroinflammation. FGF23 upregulation, in addition, was observed in response to the Lyme disease bacterium. B. burgdorferi exposure also downregulated many FGFs including FGF 5, 7, 9, 11, 13, 16, 20 and 21. Some of the upregulated FGFs have been implicated in major depressive disorder (MDD) or dementia development, while the downregulated ones have been demonstrated to have protective roles in epilepsy, Parkinson's disease, Alzheimer's disease, spinal cord injury, blood-brain barrier stability, and others.
In this study we show that FGFRs and FGFs are novel inducers of inflammatory mediators in Lyme neuroborreliosis. It is likely that an unresolved, long-term (neuro)-Lyme infection can contribute to the development of other neurologic conditions in susceptible individuals either by augmenting pathogenic FGFs or by suppressing ameliorative FGFs or both.
伯氏疏螺旋体引起的莱姆神经Borreliosis 影响中枢神经系统（CNS）和周围神经系统（PNS）。CNS 表现，特别是在后期，可能模仿/引起许多其他神经疾病，包括精神疾病、痴呆症等，可能具有神经炎症基础。然而，与莱姆神经Borreliosis 相关的致病机制尚不完全清楚。
在这项研究中，我们使用原代恒河猴小胶质细胞培养物，探索了几种成纤维细胞生长因子受体（FGFR）和成纤维细胞生长因子（FGF）在与活伯氏疏螺旋体暴露相关的神经炎症中的作用。使用 FGFR 特异性 siRNA 和抑制剂、定制抗体阵列、ELISA、免疫荧光和显微镜，全面分析了这些分子在伯氏疏螺旋体引起的小胶质细胞神经炎症中的作用。
小胶质细胞中 FGFR1-3 的表达在受到伯氏疏螺旋体的刺激后上调。使用 siRNA 和三种不同的抑制剂抑制 FGFR1、2 和 3 的信号转导表明，FGFR 信号在对莱姆病细菌的反应中具有促炎作用。FGFR1 的激活也有助于非活性伯氏疏螺旋体介导的神经炎症。通过定制的抗体阵列对伯氏疏螺旋体条件培养基进行分析表明，几种 FGFs 被活细菌诱导，包括 FGF6、FGF10 和 FGF12，它们反过来诱导 IL-6 和/或 CXCL8，表明具有促炎性质。据我们所知，这也是 FGF6 和 FGF12 首次被描述在中枢神经系统神经炎症中的作用。此外，FGFR23 的上调也观察到对莱姆病细菌的反应。伯氏疏螺旋体的暴露也下调了许多 FGFs，包括 FGF5、7、9、11、13、16、20 和 21。一些上调的 FGFs 与重度抑郁症（MDD）或痴呆症的发展有关，而下调的 FGFs 已被证明在癫痫、帕金森病、阿尔茨海默病、脊髓损伤、血脑屏障稳定性等方面具有保护作用。
在这项研究中，我们表明 FGFRs 和 FGFs 是莱姆神经Borreliosis 中炎症介质的新型诱导物。未解决的长期（神经）莱姆感染可能通过增强致病性 FGFs 或通过抑制改善性 FGFs 或两者兼而有之，导致易感个体中其他神经疾病的发展。
