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Bioinformatic analysis identifies RGS10 as a modulator of BV-2 cell migration

ABSTRACT: Regulator of G protein signaling 10 (RGS10) is a GTPase activating protein, selective for Gαi, that has been proposed to play a role in suppressing microglial-driven neuroinflammation. RGS10 expression in microglia is suppressed by inflammatory stimuli and aging, and loss of RGS10 is associated with increased cytokine expression and neurodegeneration. Conversely, RGS10 overexpression provides protection against inflammatory stimuli in rodent models, however the mechanisms by which RGS10 exerts this protective effect are unknown. To understand the neuroprotective functions of RGS10 in microglia, we completed RNA-Seq analysis in the murine microglial cell line BV-2 with intact (BV-2WT) and absent (RGS10-/-) RGS10 expression under basal and IFNγ-treated conditions. RGS10 loss altered expression of 1,579 genes in unstimulated cells and 2,142 genes under IFNγ-stimulated conditions. In addition to changes in GPCR signaling, altered processes in RGS10-/- cells, under basal and stimulated conditions, included cell migration, adhesion, cytokine production and cell development. Key cell adhesion genes such as Mmp9 and Thbs1 were downregulated in RGS10-/- cells regardless of stimuli. Other genes such as Icam1 and Il1b displayed significantly lower expression only in IFNγ-stimulated RGS10-/- cells compared to their WT counterpart. Loss of RGS10 increased BV-2 cell migration, and IFNγ stimulation led to a reduction in migration of both BV-2WT and RGS10-/- cells. The effect of RGS10 on migration could only partially be blocked by the Gαi inhibitor Pertussis toxin (PTX), suggesting involvement of both G protein-dependent and -independent mechanisms. Altogether, these results suggest a novel role for RGS10 in reducing microglial migration through regulation of cell adhesion genes.

ORGANISM(S): Mus musculus

PROVIDER: GSE301244 | GEO | 2025/07/08

REPOSITORIES: GEO

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Project description:The aging process is marked by a time-dependent deterioration in cellular functions, particularly the immune and neural systems. Understanding the phenotype acquisition of microglia, the sentinel immune cells of the brain, is crucial for understanding the nature of age-related neurological diseases. However, the specific phenotype adopted by microglia during aging remains a subject of debate and is contingent on the chosen experimental model. To address these unresolved questions, we employed a novel and highly controlled approach utilizing long-term cultivated BV-2 microglia, exempted of additional external stimuli. Our findings revealed that aged microglial cells, in comparison to their younger counterparts, acquire a distinct gene expression profile, primarily characterized by alterations in microglial immune response. Indeed, pro-inflammatory stimulated aged and young BV-2 microglia exhibited similar transcriptomic profiles, yet the response intensity to stimulus was markedly muted in the aged microglia. Functional neurotoxic assays confirmed diminished neuronal death in coculture with aged, activated microglia, underscoring a compromised immune response. Furthermore, a subsequent comparative analysis of aged BV-2 microglia with established transcriptomic microglial datasets from aged mice and humans identified 13 overlapping genes, laying the foundation for identifying core microglial aging signature. Particularly noteworthy were SLC16A3 and P2RY13, which consistently exhibited upregulation and downregulation, respectively, across all datasets. Additionally, four other genes—CAPG, LGALS3BP, NRIP1, and P2RY12—were found to share regulatory patterns in response to both aging and extrinsic activation. In-depth investigation focused on SLC16A3, encoding the high-affinity lactate transporter MCT4, revealed disruptions in extracellular acidification rate and lactate concentration with age. Microglial purine sensing and motility capacities, regulated by P2RY12/P2RY13, displayed age-related alterations. Remarkably, protein analysis in human brain tissue validated the observed upregulation of MCT4 and downregulation of P2RY12 in aged microglia. In conclusion, our study unveils a distinct phenotype in aged microglia characterized by compromised immune responsiveness. Through the integration of in vitro cultured BV-2 microglia with primary microglia datasets, we identify critical molecular determinants of microglial cellular aging confirmed in human aged brain tissue. This comprehensive approach offers potential insights for understanding and potentially reprogramming aged microglia, with implications for combating age-related neurological disorders.

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Bioinformatic analysis identifies RGS10 as a modulator of BV-2 cell migration

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