Neuroinflammation is a hallmark of many neurodegenerative diseases (NDs) and plays a fundamental role in mediating the onset and progression of disease. Microglia, which function as first-line immune guardians of the central nervous system (CNS), are the central drivers of neuroinflammation. Numerous human postmortem studies and in vivo imaging analyses have shown chronically activated microglia in patients with various acute and chronic neuropathological diseases. While microglial activation is a common feature of many NDs, the exact role of microglia in various pathological states is complex and often contradictory. However, there is a consensus that microglia play a biphasic role in pathological conditions, with detrimental and protective phenotypes, and the overall response of microglia and the activation of different phenotypes depends on the nature and duration of the inflammatory insult, as well as the stage of disease development. This review provides a comprehensive overview of current research on the various microglia phenotypes and inflammatory responses in health, aging, and NDs, with a special emphasis on the heterogeneous phenotypic response of microglia in acute and chronic diseases such as hemorrhagic stroke (HS), Alzheimer’s disease (AD), and Parkinson’s disease (PD). The primary focus is translational research in preclinical animal models and bulk/single-cell transcriptome studies in human postmortem samples. Additionally, this review covers key microglial receptors and signaling pathways that are potential therapeutic targets to regulate microglial inflammatory responses during aging and in NDs. Additionally, age-, sex-, and species-specific microglial differences will be briefly reviewed.

Regulator of G-protein signaling (RGS) proteins are GTPase activating proteins (GAPs) of heterotrimeric G-proteins that alter the amplitude and kinetics of receptor-promoted signaling. In this study we defined the G-protein α-subunit selectivity of purified Sf9 cell-derived R7 proteins, a subfamily of RGS proteins (RGS6, -7, -9, and -11) containing a Gγ-like (GGL) domain that mediates dimeric interaction with Gβ₅. Gβ₅/R7 dimers stimulated steady state GTPase activity of Gα-subunits of the G_i family, but not of Gα_q or Gα₁₁, when added to proteoliposomes containing M2 or M1 muscarinic receptor-coupled G-protein heterotrimers. Concentration effect curves of the Gβ₅/R7 proteins revealed differences in potencies and efficacies toward Gα-subunits of the G_i family. Although all four Gβ₅/R7 proteins exhibited similar potencies toward Gα_o, Gβ₅/RGS9 and Gβ₅/RGS11 were more potent GAPs of Gα_i1, Gα_i2, and Gα_i3 than were Gβ₅/RGS6 and Gβ₅/RGS7. The maximal GAP activity exhibited by Gβ₅/RGS11 was 2- to 4-fold higher than that of Gβ₅/RGS7 and Gβ₅/RGS9, with Gβ₅/RGS6 exhibiting an intermediate maximal GAP activity. Moreover, the less efficacious Gβ₅/RGS7 and Gβ₅/RGS9 inhibited Gβ₅/RGS11-stimulated GTPase activity of Gα_o. Therefore, R7 family RGS proteins are G_i family-selective GAPs with potentially important differences in activities.

Lysophosphatidic acid (LPA) is an extracellular signaling mediator with a broad range of cellular responses. Three G-protein-coupled receptors (Edg-2, -4, and -7) have been identified as receptors for LPA. In this study, the ectophosphatase lipid phosphate phosphatase 1 (LPP1) has been shown to down-regulate LPA-mediated mitogenesis. Furthermore, using degradation-resistant phosphonate analogs of LPA and stereoselective agonists of the Edg receptors we have demonstrated that the mitogenic and platelet aggregation responses to LPA are independent of Edg-2, -4, and -7. Specifically, we found that LPA degradation is insufficient to account for the decrease in LPA potency in mitogenic assays, and the stereoselectivity observed at the Edg receptors is not reflected in mitogenesis. Additionally, RH7777 cells, which are devoid of Edg-2, -4, and -7 receptor mRNA, have a mitogenic response to LPA and LPA analogs. Finally, we have determined that the ligand selectivity of the platelet aggregation response is consistent with that of mitogenesis, but not with Edg-2, -4, and -7.

RGS10 is an important regulator of cell survival and chemoresistance in ovarian cancer. We recently showed that RGS10 transcript expression is suppressed during acquired chemoresistance in ovarian cancer. The suppression of RGS10 is due to DNA hypermethylation and histone deacetylation, two important mechanisms that contribute to silencing of tumor suppressor genes during cancer progression. Here, we fully investigate the molecular mechanisms of epigenetic silencing of RGS10 expression in chemoresistant A2780-AD ovarian cancer cells. We identify two important epigenetic regulators, HDAC1 and DNMT1, that exhibit aberrant association with RGS10 promoters in chemoresistant ovarian cancer cells. Knockdown of HDAC1 or DNMT1 expression, and pharmacological inhibition of DNMT or HDAC enzymatic activity, significantly increases RGS10 expression and cisplatin-mediated cell death. Finally, DNMT1 knock down also decreases HDAC1 binding to the RGS10 promoter in chemoresistant cells, suggesting HDAC1 recruitment to RGS10 promoters requires DNMT1 activity. Our results suggest that HDAC1 and DNMT1 contribute to the suppression of RGS10 during acquired chemoresistance and support inhibition of HDAC1 and DNMT1 as an adjuvant therapeutic approach to overcome ovarian cancer chemoresistance.