Jesudasan Sam Joshva Baskar, Gupta Somnath J, Churchward Matthew A, Todd Kathryn G, Winship Ian R
Neurochemical Research Unit, Department of Psychiatry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, Canada.
Front Cell Neurosci. 2021 Apr 6;15:634020. doi: 10.3389/fncel.2021.634020. eCollection 2021.
Microglia are the primary cells in the central nervous system that identify and respond to injury or damage. Such a perturbation in the nervous system induces the release of molecules including ATP and glutamate that act as damage-associated molecular patterns (DAMPs). DAMPs are detected by microglia, which then regulate the inflammatory response in a manner sensitive to their surrounding environment. The available data indicates that ATP and glutamate can induce the release of pro inflammatory factors TNF (tumor necrosis factor), IL-1β (interleukin 1 beta), and NO (nitric oxide) from microglia. However, non-physiological concentrations of ATP and glutamate were often used to derive these insights. Here, we have compared the response of spinal cord microglia (SM) relative to brain microglia (BM) using physiologically relevant concentrations of glutamate and ATP that mimic injured conditions in the central nervous system. The data show that ATP and glutamate are not significant modulators of the release of cytokines from either BM or SM. Consistent with previous studies, spinal microglia exhibited a general trend toward reduced release of inflammatory cytokines relative to brain-derived microglia. Moreover, we demonstrate that the responses of microglia to these DAMPs can be altered by modifying the biochemical milieu in their surrounding environment. Preconditioning brain derived microglia with media from spinal cord derived mixed glial cultures shifted their release of IL-1ß and IL-6 to a less inflammatory phenotype consistent with spinal microglia.
小胶质细胞是中枢神经系统中识别并对损伤作出反应的主要细胞。神经系统中的这种扰动会诱导包括三磷酸腺苷（ATP）和谷氨酸在内的分子释放，这些分子作为损伤相关分子模式（DAMPs）发挥作用。小胶质细胞能检测到DAMPs，然后以对其周围环境敏感的方式调节炎症反应。现有数据表明，ATP和谷氨酸可诱导小胶质细胞释放促炎因子肿瘤坏死因子（TNF）、白细胞介素1β（IL-1β）和一氧化氮（NO）。然而，这些见解往往是通过使用非生理浓度的ATP和谷氨酸得出的。在此，我们使用模拟中枢神经系统损伤状况的生理相关浓度的谷氨酸和ATP，比较了脊髓小胶质细胞（SM）与脑小胶质细胞（BM）的反应。数据显示，ATP和谷氨酸对BM或SM释放细胞因子均无显著调节作用。与先前的研究一致，相对于脑源性小胶质细胞，脊髓小胶质细胞表现出炎症细胞因子释放减少的总体趋势。此外，我们证明，通过改变小胶质细胞周围环境的生化环境，可以改变其对这些DAMPs的反应。用脊髓来源的混合胶质细胞培养物的培养基预处理脑源性小胶质细胞，可使其白细胞介素-1β（IL-1ß）和白细胞介素-6（IL-6）的释放转变为与脊髓小胶质细胞一致的炎症性较低的表型。
