Tissue environment plays a powerful role in establishing and maintaining the distinct phenotypes of resident macrophages, but the underlying molecular mechanisms remain poorly understood. Here, we ...characterized transcriptomic and epigenetic changes in repopulating liver macrophages following acute Kupffer cell depletion as a means to infer signaling pathways and transcription factors that promote Kupffer cell differentiation. We obtained evidence that combinatorial interactions of the Notch ligand DLL4 and transforming growth factor-b (TGF-β) family ligands produced by sinusoidal endothelial cells and endogenous LXR ligands were required for the induction and maintenance of Kupffer cell identity. DLL4 regulation of the Notch transcriptional effector RBPJ activated poised enhancers to rapidly induce LXRα and other Kupffer cell lineage-determining factors. These factors in turn reprogrammed the repopulating liver macrophage enhancer landscape to converge on that of the original resident Kupffer cells. Collectively, these findings provide a framework for understanding how macrophage progenitor cells acquire tissue-specific phenotypes.
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•Determinants of Kupffer cell identity are inferred from dynamic enhancer landscapes•DLL4 activates poised enhancers to induce Kupffer cell lineage-determining factors•LXRα induced by DLL4 drives subsequent activation of Kupffer cell enhancers•TGF-β and desmosterol regulate SMADs and LXRs to maintain Kupffer cell identity
Tissue environment has an instructive role in establishing resident macrophage phenotypes. Sakai et al. provide evidence for a two-step model in which liver-derived signals that include DLL4, TGF-β, and desmosterol induce Kupffer cell (liver-resident macrophage) differentiation by regulating the expression and activities of RBPJ, SMADs, and LXRα.
The contribution of chronic peripheral inflammation to the pathogenesis of neurodegenerative diseases is an outstanding question. Sustained activation of the peripheral innate and adaptive immune ...systems occurs in the context of a broad array of disorders ranging from chronic infectious diseases to autoimmune and metabolic diseases. In addition, progressive systemic inflammation is increasingly recognized during aging. Peripheral immune cells could potentially modulate the cellular brain environment via the secretion of soluble molecules. There is an ongoing debate whether peripheral immune cells have the potential to migrate into the brain under certain permissive circumstances. In this perspective, we discuss the possible contribution of chronic peripheral inflammation to the pathogenesis of age-related neurodegenerative diseases with a focus on microglia, the resident immune cells of the brain parenchyma.
Depression is a common and disabling comorbidity in rheumatoid arthritis that not only decreases the likelihood of remission and treatment adherence but also increases the risk of disability and ...mortality in patients with rheumatoid arthritis. Compelling data that link immune mechanisms to major depressive disorder indicate possible common mechanisms that drive the pathology of the two conditions. Preclinical evidence suggests that pro-inflammatory cytokines, which are prevalent in rheumatoid arthritis, have various effects on monoaminergic neurotransmission, neurotrophic factors and measures of synaptic plasticity. Neuroimaging studies provide insight into the consequences of inflammation on the brain (for example, on neural connectivity), and clinical trial data highlight the beneficial effects of immune modulation on comorbid depression. Major depressive disorder occurs more frequently in patients with rheumatoid arthritis than in the general population, and major depressive disorder also increases the risk of a future diagnosis of rheumatoid arthritis, further highlighting the link between rheumatoid arthritis and major depressive disorder. This Review focuses on interactions between peripheral and central immunobiological mechanisms in the context of both rheumatoid arthritis and major depressive disorder. Understanding these mechanisms will provide a basis for future therapeutic development, not least in depression.
People living with HIV are affected by the chronic consequences of neurocognitive impairment (NCI) despite antiretroviral therapies that suppress viral replication, improve health and extend life. ...Furthermore, viral suppression does not eliminate the virus, and remaining infected cells may continue to produce viral proteins that trigger neurodegeneration. Comorbidities such as diabetes mellitus are likely to contribute substantially to CNS injury in people living with HIV, and some components of antiretroviral therapy exert undesirable side effects on the nervous system. No treatment for HIV-associated NCI has been approved by the European Medicines Agency or the US Food and Drug Administration. Historically, roadblocks to developing effective treatments have included a limited understanding of the pathophysiology of HIV-associated NCI and heterogeneity in its clinical manifestations. This heterogeneity might reflect multiple underlying causes that differ among individuals, rather than a single unifying neuropathogenesis. Despite these complexities, accelerating discoveries in HIV neuropathogenesis are yielding potentially druggable targets, including excessive immune activation, metabolic alterations culminating in mitochondrial dysfunction, dysregulation of metal ion homeostasis and lysosomal function, and microbiome alterations. In addition to drug treatments, we also highlight the importance of non-pharmacological interventions. By revisiting mechanisms implicated in NCI and potential interventions addressing these mechanisms, we hope to supply reasons for optimism in people living with HIV affected by NCI and their care providers.
Neurons are the longest-lived cells in our bodies and lack DNA replication, which makes them reliant on a limited repertoire of DNA repair mechanisms to maintain genome fidelity. These repair ...mechanisms decline with age, but we have limited knowledge of how genome instability emerges and what strategies neurons and other long-lived cells may have evolved to protect their genomes over the human life span. A targeted sequencing approach in human embryonic stem cell-induced neurons shows that, in neurons, DNA repair is enriched at well-defined hotspots that protect essential genes. These hotspots are enriched with histone H2A isoforms and RNA binding proteins and are associated with evolutionarily conserved elements of the human genome. These findings provide a basis for understanding genome integrity as it relates to aging and disease in the nervous system.
Microglia are specialized brain-resident macrophages that play crucial roles in brain development, homeostasis, and disease. However, until now, the ability to model interactions between the human ...brain environment and microglia has been severely limited. To overcome these limitations, we developed an in vivo xenotransplantation approach that allows us to study functionally mature human microglia (hMGs) that operate within a physiologically relevant, vascularized immunocompetent human brain organoid (iHBO) model. Our data show that organoid-resident hMGs gain human-specific transcriptomic signatures that closely resemble their in vivo counterparts. In vivo two-photon imaging reveals that hMGs actively engage in surveilling the human brain environment, react to local injuries, and respond to systemic inflammatory cues. Finally, we demonstrate that the transplanted iHBOs developed here offer the unprecedented opportunity to study functional human microglia phenotypes in health and disease and provide experimental evidence for a brain-environment-induced immune response in a patient-specific model of autism with macrocephaly.
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•Xenotransplanted brain organoids as in vivo platform for studying human microglia (hMGs)•hMGs gain human-specific transcriptomic signatures and assume in-vivo-like identities•hMGs engage in surveilling the human brain environment and react to perturbations•A patient-derived model reveals a brain-environment-induced immune response in autism
Schafer et al. present an organoid-based xenotransplantation platform to study human brain-environment-dependent and disease-associated microglia phenotypes under in vivo conditions.
The growing recognition of a dichotomous role of astrocytes in neurodegenerative processes has heightened the need for unraveling distinct astrocytic subtypes in neurological disorders. In multiple ...system atrophy (MSA), a rare, rapidly progressing atypical Parkinsonian disease characterized by increased astrocyte reactivity. However the specific contribution of astrocyte subtypes to neuropathology remains elusive. Hence, we first set out to profile glial fibrillary acidic protein levels in astrocytes across the human post mortem motor cortex, putamen, and substantia nigra of MSA patients and observed an overall profound astrocytic response. Matching the post mortem human findings, a similar astrocytic phenotype was present in a transgenic MSA mouse model. Notably, MSA mice exhibited a decreased expression of the glutamate transporter 1 and glutamate aspartate transporter in the basal ganglia, but not the motor cortex. We developed an optimized astrocyte isolation protocol based on magnetic-activated cell sorting via ATPase Na+/K+ transporting subunit beta 2 and profiled the transcriptomic landscape of striatal and cortical astrocytes in transgenic MSA mice. The gene expression profile of astrocytes in the motor cortex displayed an anti-inflammatory signature with increased oligodendroglial and pro-myelinogenic expression pattern. In contrast, striatal astrocytes were defined by elevated pro-inflammatory transcripts accompanied by dysregulated genes involved in homeostatic functions for lipid and calcium metabolism. These findings provide new insights into a region-dependent, dichotomous astrocytic response-potentially beneficial in the cortex and harmful in the striatum-in MSA suggesting a differential role of astrocytes in MSA-related neurodegenerative processes.
Neuroinflammation and oligodendroglial cytoplasmic α‐synuclein (α‐syn) inclusions (GCIs) are important neuropathological characteristics of multiple system atrophy (MSA). GCIs are known to interfere ...with oligodendroglial maturation and consequently result in myelin loss. The neuroinflammatory phenotype in the context of MSA, however, remains poorly understood. Here, we demonstrate MSA‐associated neuroinflammation being restricted to myeloid cells and tightly linked to oligodendroglial α‐syncleinopathy. In human putaminal post‐mortem tissue of MSA patients, neuroinflammation was observed in white matter regions only. This locally restricted neuroinflammation coincided with elevated numbers of α‐syn inclusions, while gray matter with less α‐synucleinopathy remained unaffected. In order to analyze the temporal pattern of neuroinflammation, a transgenic mouse model overexpressing human α‐syn under the control of an oligodendrocyte‐specific myelin basic protein (MBP) promoter (MBP29‐hα‐syn mice) was assessed in a pre‐symptomatic and symptomatic disease stage. Strikingly, we detected an increased neuroinflammation in regions with a high α‐syn load, the corpus callosum and the striatum, of MBP29‐hα‐syn mice, already at a pre‐symptomatic stage. Furthermore, this inflammatory response was restricted to myeloid cells being highly proliferative and showing an activated, phagocytic phenotype. In contrast, severe astrogliosis was observed only in gray matter regions of MSA patients as well as MBP29‐hα‐syn mice. To further characterize the influence of oligodendrocytes on initiation of the myeloid immune response, we performed RNA sequencing analysis of α‐syn overexpressing primary oligodendrocytes. A distinct gene expression profile including upregulation of cytokines important for myeloid cell attraction and proliferation was detected in α‐syn overexpressing oligodendrocytes. Additionally, microdissected tissue of MBP29‐hα‐syn mice exhibited a similar cellular gene expression profile in white matter regions even pre‐symptomatically. Collectively, these results imply an early crosstalk between neuroinflammation and oligodendrocytes containing α‐syn inclusions leading to an immune response locally restricted to white matter regions in MSA.
Multiple system atrophy (MSA) is a rare atypical parkinsonian disorder characterized by a rapidly progressing clinical course and at present without any efficient therapy. Neuropathologically, myelin ...loss and neurodegeneration are associated with α-synuclein accumulation in oligodendrocytes, but underlying pathomechanisms are poorly understood. Here, we analyzed the impact of oligodendrocytic α-synuclein on the formation of myelin sheaths to define a potential interventional target for MSA. Post-mortem analyses of MSA patients and controls were performed to quantify myelin and oligodendrocyte numbers. As pre-clinical models, we used transgenic MSA mice, a myelinating stem cell-derived oligodendrocyte-neuron co-culture, and primary oligodendrocytes to determine functional consequences of oligodendrocytic α-synuclein overexpression on myelination. We detected myelin loss accompanied by preserved or even increased numbers of oligodendrocytes in post-mortem MSA brains or transgenic mouse forebrains, respectively, indicating an oligodendrocytic dysfunction in myelin formation. Corroborating this observation, overexpression of α-synuclein in primary and stem cell-derived oligodendrocytes severely impaired myelin formation, defining a novel α-synuclein-linked pathomechanism in MSA. We used the pro-myelinating activity of the muscarinic acetylcholine receptor antagonist benztropine to analyze the reversibility of the myelination deficit. Transcriptome profiling of primary pre-myelinating oligodendrocytes demonstrated that benztropine readjusts myelination-related processes such as cholesterol and membrane biogenesis, being compromised by oligodendrocytic α-synuclein. Additionally, benztropine restored the α-synuclein-induced myelination deficit of stem cell-derived oligodendrocytes. Strikingly, benztropine also ameliorated the myelin deficit in transgenic MSA mice, resulting in a prevention of neuronal cell loss. In conclusion, this study defines the α-synuclein-induced myelination deficit as a novel and crucial pathomechanism in MSA. Importantly, the reversible nature of this oligodendrocytic dysfunction opens a novel avenue for an intervention in MSA.
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