Microglia and CD206+ border-associated mouse macrophages maintain their embryonic origin during Alzheimer’s disease

Brain microglia and border-associated macrophages (BAMs) display distinct spatial, developmental, and phenotypic features. Although at steady state, the origins of distinct brain macrophages are well-documented, the dynamics of their replenishment in neurodegenerative disorders remain elusive, particularly for activated CD11c+ microglia and BAMs. In this study, we conducted a comprehensive fate-mapping analysis of murine microglia and BAMs and their turnover kinetics during Alzheimer’s disease (AD) progression. We used a novel inducible AD mouse model to investigate the contribution of bone marrow (BM) cells to the pool of fetal-derived brain macrophages during the development of AD. We demonstrated that microglia remain a remarkably stable embryonic-derived population even during the progression of AD pathology, indicating that neither parenchymal macrophage subpopulation originates from, nor is replenished by, BM-derived cells. At the border-associated brain regions, bona fide CD206+ BAMs are minimally replaced by BM-derived cells, and their turnover rates are not accelerated by AD. In contrast, all other myeloid cells are swiftly replenished by BM progenitors. This information further elucidates the turnover kinetics of these cells not only at steady state, but also in neurodegenerative diseases, which is crucial for identifying potential novel therapeutic targets.

Immunophilin Ligands Modulate Phagocytosis and Viral 2 Replication in HIV-Infected Macrophages

(1) Background: HIV-associated neurocognitive disorders (HAND) can occur as a result of HIV-mediated neuroinflammation and affect people living with HIV (PWH) despite advances in combination antiretroviral therapy (cART). Brain macrophages have been implicated as a source of virus and neurotoxic factors. In this study, we examined the potential role of the immunophilin ligands rapamycin and FK506 in modulating neuroinflammation caused by infected macrophages. (2) Methods: Monocytes were isolated from blood samples from three different blood donors and were differentiated into macrophages (MDMs). These cells were subsequently infected with HIV and treated with combinations of an antiretroviral (ARV) cocktail (raltegravir, emtricitabine, and tenofovir), FK506, and rapamycin. Immunocytochemistry and RT-qPCR were used to analyze the phagocytosis of amyloid beta and the expression of macrophage phenotype-associated markers such as Iba1, TREM2, and IL-6. Viral replication was measured using p24 ELISA. (3) Results: Viral replication among infected MDMs as indicated by p24 levels was positively correlated with Iba1 levels and negatively correlated with IL-6 expression. However, infected MDMs showed lower Iba1 levels than non-infected cells. Rapamycin treatment appeared to lower p24 levels across all donors. Phagocytosis was associated with higher Iba1 levels and was impaired in rapamycin-treated MDMs. (4) Conclusions: Rapamycin seemed to protect against viral replication. However, decreased replication was correlated with a decrease in phagocytic activity. Iba1 may be involved in phagocytosis and HIV infection while IL-6 appeared to indicate protective effects against replication.

Microglia and border-associated mouse macrophages maintain their embryonic origin during Alzheimers disease

Brain microglia and border-associated macrophages (BAMs) display distinct spatial, developmental, and phenotypic features. Although at steady-state, the origins of distinct brain macrophages are well-documented, the dynamics of their replenishment in neurodegenerative disorders remain elusive, particularly for disease-associated microglia (DAMs) and BAMs. In this study, we conducted a comprehensive fate-mapping analysis of murine microglia and BAMs and their turnover kinetics during Alzheimers disease (AD) progression. We used a novel inducible AD mouse model to investigate the contribution of bone marrow cells to the pool of foetal-derived brain macrophages during the development of AD. We demonstrated that microglia and DAMs remain a remarkably stable embryonic-derived population even during the progression of AD pathology, indicating that neither parenchymal macrophage subpopulation originates from, nor are replenished by, monocytes. At the border-associated brain regions, bona fide CD206+ BAMs are minimally replaced by monocytes, and their turnover rates are not accelerated by AD. In contrast, all other myeloid cells are swiftly replenished by bone marrow progenitors. This information further elucidates the turnover kinetics of these cells not only at steady-state, but also in neurodegenerative diseases, which is crucial for identifying potential novel therapeutic targets.

The natural anti-inflammatory sesquiterpene lactone achillolide A reduces atopic dermatitis in a murine model

Plant-derived substances have been shown to affect potential targets in inflammatory diseases. We have previously purified from the desert plant Achillea fragrantissima, a sesquiterpene lactone named achillolide A, and demonstrated its anti-inflammatory activities in cultured brain macrophages named microglial cells. In the present study, we further investigated achillolide A in alleviating atopic dermatitis, a chronic and recurring inflammatory skin disease. We investigated achillolide A for its in vivo anti-inflammatory activity using the oxazolone model of atopic dermatitis in mice, in which oxazolone induces ear swelling. Our results show that mice treated with achillolide A showed a significant decrease in the oxazolone-induced ear swelling. Since macrophages are inflammatory cells that play a pivotal role in the pathogenesis of atopic dermatitis, the anti-inflammatory effects of achillolide A were also studied in spleen cells. We demonstrated that achillolide A reduced the levels of LPS-induced inflammatory cytokines IL-2, IL-6, TNFα, IFNγ and IL-12 that were secreted from cultured splenocytes. These data suggest that achillolide A should be considered for further research in treating atopic dermatitis.

Methamphetamine Increases the Proportion of SIV-Infected Microglia/Macrophages, Alters Metabolic Pathways, and Elevates Cell Death Pathways: A Single-Cell Analysis

Both substance use disorder and HIV infection continue to affect many individuals. Both have untoward effects on the brain, and the two conditions often co-exist. In the brain, macrophages and microglia are infectable by HIV, and these cells are also targets for the effects of drugs of abuse, such as the psychostimulant methamphetamine. To determine the interaction of HIV and methamphetamine, we isolated microglia and brain macrophages from SIV-infected rhesus monkeys that were treated with or without methamphetamine. Cells were subjected to single-cell RNA sequencing and results were analyzed by statistical and bioinformatic analysis. In the animals treated with methamphetamine, a significantly increased proportion of the microglia and/or macrophages were infected by SIV. In addition, gene encoding functions in cell death pathways were increased, and the brain-derived neurotropic factor pathway was inhibited. The gene expression patterns in infected cells did not cluster separately from uninfected cells, but clusters comprised of microglia and/or macrophages from methamphetamine-treated animals differed in neuroinflammatory and metabolic pathways from those comprised of cells from untreated animals. Methamphetamine increases CNS infection by SIV and has adverse effects on both infected and uninfected microglia and brain macrophages, highlighting the dual and interacting harms of HIV infection and drug abuse on the brain.