Oligodendroglia play a critical role in CNS homeostasis by myelinating neuronal axons in their mature stages. Dysfunction in this lineage occurs when early stage OPCs are not able to differentiate to replace dying Mature Myelinating Oligodendrocytes. Many hypotheses exist as to why de- and hypo-myelinating disorders and diseases occur. In this review, we present data to show that oligodendroglia can adopt components of the immune proteasome under inflammatory conditions. The works reviewed further reflect that these immune-component expressing oligodendroglia can in fact function as antigen presenting cells, phagocytosing foreign entities and presenting them via MHC II to activate CD4+ T cells. Additionally, we hypothesize, based on the limited literature, that the adoption of immune components by oligodendroglia may contribute to their stalled differentiation in the context of these disorders and diseases. The present review will underline: (1) Mechanisms of neuroinflammation in diseases associated with Immune Oligodendroglia; (2) the first associations between the immune proteasome and oligodendroglia and the subtle distinctions between these works; (3) the suggested functionality of these cells as it is described by current literature; and (4) the hypothesized consequences on metabolism. In doing so we aim to shed light on this fairly under-explored cell type in hopes that study of their functionality may lead to further mechanistic understanding of hypo- and de-myelinating neuroinflammatory disorders and diseases.
Repeated stress can lead to the development of anxiety and is considered a risk factor for major depressive disorder (MDD). Clinical studies and animal models of repeated and chronic stress have reported that symptom severity is correlated with microglial activation and upregulation of neuroinflammatory cytokine signaling in brain areas implicated in mood regulation. Despite mounting evidence implicating impairments of neuroplasticity and synaptic signaling deficits into the pathophysiology of stress-related mental disorders, whether microglial activation modulates neuronal homeostasis in response to chronic stress has been debated. Here, using the repeated social defeat stress (RSDS) mouse model we demonstrate that microglial activation and related inflammatory responses are regulating neuronal plasticity associated with depressive-like behavior. Specifically, we show that chronic stress induces a swift activation and proliferation of microglia as well as macrophage infiltration in the mPFC, which are spatially related to neuronal activation. Moreover, we report a remarkable association of microglial spectrum of reactivity and concomitant inflammatory responses with susceptibility or resilience to chronic stress. In addition, we find that exposure to chronic stress exacerbates phagocytosis of synaptic elements and significant neuronal plasticity deficits associated with depressive-like behavior. Importantly, by utilizing two different CSF1R inhibitors (the brain penetrant PLX5622 and the non-penetrant PLX73086) we determine the contributions of microglial and infiltrating macrophages in the depression pathophenotype. Our findings highlight a crucial role for microglia (and secondarily macrophages) in catalyzing the pathological manifestations of depression in response to chronic stress by promoting neuroinflammation and neuronal deficits in mPFC.
ID 19298 Poster Board 63 Background: Major Depressive Disorder (MDD) is a complex and heterogenous psychiatric disorder affecting more than 350 million people worldwide. Though the mechanisms underlying MDD are not fully understood, a subset of depressive patients can manifest chronic neuroinflammatory responses. In addition, brain-imaging studies in MDD patients have provided evidence of white matter reductions and such changes are hypothesized to lead to disruption of Oligodendroglial (OLN) homeostatic mechanisms, resulting in destabilization of emotional/cognitive circuitry. Recent work shows that a subset of OLN may adopt immune phenotypes (ImOL). The present goal of the study is to investigate whether these histopathological alterations are linked with chronic inflammation through a culture systems and a mouse model of depression.Methods In vivo: The Repeated Social Defeat Stress (RSDS) paradigm (10 days) was used to induce depressive-like behavior in 8-12-week-old male CX3CR1-GFP + and CSPG4-EGFP + mice. Behavioral tasks (BH) were performed to stratify the defeated mice to susceptible (S; depressive-like) and resilient (R; non-depressive) to stress groups. The study focuses on the stress-affected prefrontal cortex (mPFC) area. PLX5622 treatment was conducted for 7 days post RSDS. In vitro: Primary OPCs were isolated from neonatal (P1-P3) mouse pups. OPCs were treated with 100 U/mL IFNgfor 48 hours before being fixed or lysed. ResultsIn vivo: Our results show that microglia become activated, expressing higher levels of pro-inflammatory markers like iNOS and CD86 in S as compared to R and Control (C) mice. We have also demonstrated that in S mice, compared to C and R, hypomyelination occurs and O4+ OLN express MHCII, P2RY12, and C3, markers typically expressed by innate immune cells. Interestingly, when treated with PLX5622, all S mice become R. In line with this, inflammatory cytokines are decreased, numbers of ImOL are rescued to control levels and hypomyelination is rescued. In vitro: OPC culture work shows that IFNg treatment is enough to cause expression of MHCII in NG2+ OPCs.Conclusions Together, our computational data in MDD patients and depression mouse model, show that OLN can adopt an immune-like phenotype which is recued when 90-95% of microglia are ablated. Additionally, our culture work confirms that the ImOL phenotype does occur in response to inflammatory cytokines.
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