Glia最新文献

Neuroinflammation, predominantly associated with glial activation and the release of various inflammatory mediators, is a vital hallmark of the pathophysiology of epilepsy. Numerous studies have indicated that identifying novel factors that diminish neuroinflammatory processes may be important for developing effective therapeutic strategies to prevent neuropathological processes and epileptogenic progression. Transient receptor potential vanilloid 5 (TRPV5) is a highly selective calcium ion channel belonging to the TRPV family. TRPV5 expression has been identified in diverse regions of the brain; however, it remains unknown how TRPV5 is implicated in the pathophysiological features of neurological diseases, including epilepsy. Herein, we show that TRPV5 expression is upregulated in the hippocampus of a pilocarpine-induced status epilepticus (PCSE) model, predominantly in activated microglia. Pharmacological inhibition of TRPV5 using econazole attenuated microglial activation, as indicated by the shift of LPS-stimulated primary hippocampal microglia to a resting state. This inhibition suppressed AKT/NF-κB signaling, reduced NLRP3 inflammasome activity, and decreased proinflammatory cytokine production. Additionally, TRPV5 inhibition reduced hippocampal microglial activation and neuroinflammation following PCSE. These findings suggest that TRPV5 contributes to the regulation of microglial activation, resulting in the suppression of microglia-derived neuroinflammation during the sub-acute phase of epilepsy. In conclusion, the present study suggests that targeting TRPV5 may offer a novel therapeutic approach to managing the neuroinflammatory processes during epileptogenic progression.

In the hypothalamus, detection of energy substrates such as glucose is essential to regulate food intake and peripheral energy homeostasis. Metabolic interactions between astrocytes and neurons via lactate exchange have been proposed as a hypothalamic glucose-sensing mechanism, but the molecular basis remains uncertain. Mouse hypothalamic astrocytes in vitro were found to exhibit a stronger glycolytic phenotype in basal conditions than cortical astrocytes. It was associated with higher protein expression levels of the Pyruvate Kinase Isoform M2 (Pkm2) and its more prominent nuclear localization. In parallel, hypothalamic astrocytes also expressed higher levels of the monocarboxylate transporter Slc16a3 (Mct4), which were dependent on Pkm2 expression. The stronger Mct4 expression in hypothalamic versus cortical astrocytes is an intrinsic characteristic, as it was also present after their direct isolation from adult mouse tissue. The high lactate release capacity of hypothalamic astrocytes was demonstrated to depend on the expression of Mct4, but not Mct1. Unlike cortical astrocytes, hypothalamic astrocytes in culture do not respond to glutamate with enhanced glycolysis, but instead, they modulate their lactate production according to glucose concentrations in an AMPK-dependent manner, an effect observed in both mouse and human hypothalamic astrocytes in vitro. Our study shows that hypothalamic and cortical astrocytes are geared to have distinct glycolytic responses to glucose and glutamate, respectively. These results reveal a metabolic specialization of astrocytes in order to fulfill distinct area-specific functions: glucose-sensing in the hypothalamus versus activity-dependent neuronal energetic supply in cortical regions.

Cerebral organoids derived from human induced pluripotent stem cells (iPSCs) are increasingly becoming essential tools to study the human brain, from understanding pathological mechanisms in neurodevelopmental, neurodegenerative, and infectious diseases to identifying genetic risks and biomarkers. To resemble the brain environment, cerebral organoids must contain microglia, the resident macrophages of the brain parenchyma that are essential for its homeostasis. As microglia derive from the yolk sac, they are not present in conventional brain organoids, which are generated by reprogramming iPSCs towards the neuroectodermal lineage and must be exogenously incorporated through a variety of strategies. Once in the organoid parenchyma, microglia must recapitulate their developmental milestones to achieve full immunocompetence, reaching a mature transcriptional profile and morphology, a tessellated distribution, efficient phagocytosis, and controlled inflammatory responses. In this review, we will summarize recent protocols that have been developed to generate human microglial-containing cerebral organoids (MCCOs), focusing on the methods used to assess the level of microglial maturation compared to their in vivo counterparts. We provide a series of recommendations to assess microglial immunocompetence using stringent quantitative approaches that will promote developing standardized protocols to culture MCCOs.

Aberrant activation of multiple cellular processes and signaling pathways is a hallmark of many neurological disorders. Understanding how these processes interact is crucial for elucidating the neuropathogenesis of these diseases. Among these, endoplasmic reticulum (ER) stress, activation of the unfolded protein response (UPR), and neuroinflammation are frequently implicated. Previously, we demonstrated that ER stress synergizes with tumor necrosis factor (TNF)-α to amplify interleukin (IL)-6 and C-C motif chemokine ligand (CCL)20 production in astrocytes through a Janus kinase 1 (JAK1)-dependent mechanism. Here, we expand on this finding by defining the scope and underlying mechanisms of this phenomenon. We show that ER stress and TNF-α cooperatively enhance inflammatory gene expression in astrocytes via a signaling axis that requires both protein kinase R (PKR)-like ER kinase (PERK) and JAK1. PERK-mediated phosphorylation of eukaryotic translation initiation factor (eIF)2α suppresses protein translation, delaying the expression of negative regulators such as NF-κB inhibitor (IκB)α and suppressor of cytokine signaling (SOCS)3 following TNF-α or oncostatin M (OSM) stimulation, respectively. Pharmacological reversal of p-eIF2α-dependent translational suppression using the small molecule integrated stress response inhibitor (ISRIB) restored IκBα and SOCS3 expression and attenuated the ER stress-induced enhancement of TNF-α- or OSM-driven inflammatory responses. Notably, astrocytes harboring a vanishing white matter-associated EIF2B5 mutation revealed that translational attenuation alone is insufficient to amplify cytokine-induced gene expression. Together, these findings identify a PERK/eIF2α/JAK1 signaling axis that sensitizes astrocytes to inflammatory cytokines, providing new mechanistic insights into the interactions between ER stress and neuroinflammation.

Cover Illustration: Oligodendrocyte binds to laminin on the perivascular basement membrane in the murine cortex at the age of postnatal day 16 (red: CC-1; green: laminin alpha-2; blue: DAPI). (See Sasaki, B., et al, https://doi.org/10.1002/glia.70027)