PDF(Pubmed)
Abstract：
Extracellular ATP (eATP) signaling through the P2X7 receptor pathway is widely believed to trigger NLRP3 inflammasome assembly in microglia, potentially contributing to depression. However, the cellular stress responses of microglia to both eATP and stress itself remain largely unexplored. Mitochondria-associated membranes (MAMs) is a platform facilitating calcium transport between the endoplasmic reticulum (ER) and mitochondria, regulating ER stress responses and mitochondrial homeostasis. This study aims to investigate how MAMs influence microglial reaction and their involvement in the development of depression-like symptoms in response to chronic social defeat stress (CSDS). CSDS induced ER stress, MAMs\' modifications, mitochondrial damage, and the formation of the IP3R3-GRP75-VDAC1 complex at the ER-mitochondria interface in hippocampal microglia, all concomitant with depression-like behaviors. Additionally, exposing microglia to eATP to mimic CSDS conditions resulted in analogous outcomes. Furthermore, knocking down GRP75 in BV2 cells impeded ER-mitochondria contact, calcium transfer, ER stress, mitochondrial damage, mitochondrial superoxide production, and NLRP3 inflammasome aggregation induced by eATP. In addition, reduced GRP75 expression in microglia of Cx3cr1CreER/+Hspa9f/+ mice lead to reduce depressive behaviors, decreased NLRP3 inflammasome aggregation, and fewer ER-mitochondria contacts in hippocampal microglia during CSDS. Here, we show the role of MAMs, particularly the formation of a tripartite complex involving IP3R3, GRP75, and VDAC1 within MAMs, in facilitating communication between the ER and mitochondria in microglia, thereby contributing to the development of depression-like phenotypes in male mice.
摘要：
通过P2X7受体途径的细胞外ATP（eATP）信号被广泛认为会触发小胶质细胞中的NLRP3炎性体组装，可能导致抑郁症。然而,小胶质细胞对eATP和应激本身的细胞应激反应仍未被研究。线粒体相关膜（MAMs）是促进内质网（ER）和线粒体之间钙运输的平台，调节内质网应激反应和线粒体稳态。这项研究旨在调查MAM如何影响小胶质细胞反应及其参与慢性社会失败压力（CSDS）的抑郁症样症状的发展。CSDS诱导的ER应激，MAMs\'修改,线粒体损伤，在海马小胶质细胞的ER-线粒体界面形成IP3R3-GRP75-VDAC1复合物,都伴随着抑郁样的行为。此外,将小胶质细胞暴露于eATP以模拟CSDS条件会导致类似的结果。此外，敲低BV2细胞中的GRP75阻碍了ER-线粒体接触，钙转移，ER压力,线粒体损伤，线粒体超氧化物的产生，和eATP诱导的NLRP3炎性体聚集。此外,Cx3cr1CreER/+Hspa9f/+小鼠小胶质细胞GRP75表达降低导致抑郁行为减少，NLRP3炎性体聚集减少，CSDS期间海马小胶质细胞内质网线粒体接触较少。这里,我们展示了MAM的作用，特别是在MAM内形成涉及IP3R3，GRP75和VDAC1的三方复合物，促进小胶质细胞内质网和线粒体之间的交流，从而促进雄性小鼠抑郁样表型的发展。
