Immune compartments at the brain’s borders in health and neurovascular diseases

Goertz, Jennifer E.; García-Bonilla, Lidia; Iadecola, Costantino; Anrather, Josef

doi:10.1007/s00281-023-00992-6

Cited by 6 publications

(5 citation statements)

References 112 publications

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“…Given the increased interest in the roles of meninges regulating brain function and the inflammatory response after stroke 62–64 , the tMPS model, not needing craniotomy and compatible with in vivo imaging, is ideally suited to address their roles in the response to thrombotic stroke.…”

Section: Discussionmentioning

confidence: 99%

A minimally invasive thrombotic stroke model to study circadian rhythm in awake mice

Marks,

Ahn,

Rai

et al. 2024

Preprint

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Experimental stroke models in rodents are essential for mechanistic studies and therapeutic development. However, these models have several limitations negatively impacting their translational relevance. Here we aimed to develop a minimally invasive thrombotic stroke model through magnetic particle delivery that does not require craniotomy, is amenable to reperfusion therapy, can be combined with in vivo imaging modalities, and can be performed in awake mice. We found that the model results in reproducible cortical infarcts within the middle cerebral artery (MCA) with cytologic and immune changes similar to that observed with more invasive distal MCA occlusion models. Importantly, the injury produced by the model was ameliorated by tissue plasminogen activator (tPA) administration. We also show that MCA occlusion in awake animals results in bigger ischemic lesions independent of day/night cycle. Magnetic particle delivery had no overt effects on physiologic parameters and systemic immune biomarkers. In conclusion, we developed a novel stroke model in mice that fulfills many requirements for modeling human stroke.

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Section: Discussionmentioning

confidence: 99%

A minimally invasive thrombotic stroke model to study circadian rhythm in awake mice

Marks,

Ahn,

Rai

et al. 2024

Preprint

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“…The presence of HIV target CCR5+ CD4 T h 1 cells in immune-rich compartments within the CNS beyond the CSF highlights their potential role in supporting viral replication. Notably, higher levels of vRNA within the dura, compared to the parenchyma, might be attributed to transitory cells draining from the brain and subarachnoid space through dural lymphatic vessels, although the possibility of resident cells in this compartment cannot be ruled out [ 33 , 59 ]. Another intriguing site is the choroid plexus stroma, positioned at the interface of peripheral blood and CSF, known to harbor macrophages and dendritic cells.…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, we studied the dura mater (dura), which represents the outermost meningeal layer and supports the meningeal lymphatics. Another important compartment we examined was the skull bone marrow (Sk BM), allowing us to assess the lymphoid niche of the calvaria [33][34][35]. To complement our investigation, we also included the draining lymph nodes of the brain, the deep cervical lymph nodes (dCLN) and the ileum as a non-CNS tissue.…”

Section: Ccr5+ Cd4 T H 1 Cells Populate Brain Parenchymamentioning

confidence: 99%

Deep analysis of CD4 T cells in the rhesus CNS during SIV infection

Elizaldi,

Verma,

et al. 2023

PLoS Pathog

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Virologic suppression with antiretroviral therapy (ART) has significantly improved health outcomes for people living with HIV, yet challenges related to chronic inflammation in the central nervous system (CNS)—known as Neuro-HIV- persist. As primary targets for HIV-1 with the ability to survey and populate the CNS and interact with myeloid cells to co-ordinate neuroinflammation, CD4 T cells are pivotal in Neuro-HIV. Despite their importance, our understanding of CD4 T cell distribution in virus-targeted CNS tissues, their response to infection, and potential recovery following initiation of ART remain limited. To address these gaps, we studied ten SIVmac251-infected rhesus macaques using an ART regimen simulating suboptimal adherence. We evaluated four macaques during the acute phase pre-ART and six during the chronic phase. Our data revealed that HIV target CCR5+ CD4 T cells inhabit both the brain parenchyma and adjacent CNS tissues, encompassing choroid plexus stroma, dura mater, and the skull bone marrow. Aligning with the known susceptibility of CCR5+ CD4 T cells to viral infection and their presence within the CNS, high levels of viral RNA were detected in the brain parenchyma and its border tissues during acute SIV infection. Single-cell RNA sequencing of CD45+ cells from the brain revealed colocalization of viral transcripts within CD4 clusters and significant activation of antiviral molecules and specific effector programs within T cells, indicating CNS CD4 T cell engagement during infection. Acute infection led to marked imbalance in the CNS CD4/CD8 ratio which persisted into the chronic phase. These observations underscore the functional involvement of CD4 T cells within the CNS during SIV infection, enhancing our understanding of their role in establishing CNS viral presence. Our findings offer insights for potential T cell-focused interventions while underscoring the challenges in eradicating HIV from the CNS, particularly in the context of sub-optimal ART.

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“…The presence of HIV target CCR5+ CD4 Th1 cells in immune-rich compartments within the CNS beyond the CSF highlights their potential role in supporting viral replication. Notably, higher levels of vRNA within the dura, compared to the parenchyma, might be attributed to transitory cells draining from the brain and subarachnoid space through dural lymphatic vessels, although the possibility of resident cells in this compartment cannot be ruled out [33,59]. Another intriguing site is the choroid plexus stroma, positioned at the interface of peripheral blood and CSF, known to harbor macrophages and dendritic cells.…”

Section: Discussionmentioning

confidence: 99%

CD4 T cell Responses in the CNS during SIV infection

Elizaldi,

Verma,

et al. 2023

Preprint

View full text Add to dashboard Cite

Virologic suppression with antiretroviral therapy (ART) has significantly improved health outcomes for people living with HIV, yet challenges related to chronic inflammation in the central nervous system (CNS) - known as Neuro-HIV- persist. As primary targets for HIV-1 with the ability to survey and populate the CNS and interact with myeloid cells to co-ordinate neuroinflammation, CD4 T cells are pivotal in Neuro-HIV. Despite their importance, our understanding of CD4 T cell distribution in virus-targeted CNS tissues, their response to infection, and potential recovery following initiation of ART remain limited. To address these gaps, we studied ten SIVmac251-infected rhesus macaques using an ART regimen simulating suboptimal adherence. We evaluated four macaques during the acute phase pre-ART and six during the chronic phase. Our data revealed that HIV target CCR5+ CD4 T cells inhabit both the brain parenchyma and adjacent CNS tissues, encompassing choroid plexus stroma, dura mater, and the skull bone marrow. Aligning with the known susceptibility of CCR5+ CD4 T cells to viral infection and their presence within the CNS, high levels of viral RNA were detected in the brain parenchyma and its border tissues during acute SIV infection. Single-cell RNA sequencing of CD45+ cells from the brain revealed colocalization of viral transcripts within CD4 clusters and significant activation of anti-viral molecules and specific effector programs within T cells, indicating CNS CD4 T cell engagement during infection. Despite viral suppression with ART, acute infection led to significant depletion of CNS CD4 T cells, persisting into the chronic phase. These findings underscore the functional involvement of CD4 T cells within the CNS during SIV infection, enhancing our understanding of their role in establishing CNS viral presence. Our results offer insights for potential T cell-focused interventions while also underscoring the challenges in eradicating HIV from the CNS, even with effective ART.

show abstract

Immune compartments at the brain’s borders in health and neurovascular diseases

Cited by 6 publications

References 112 publications

A minimally invasive thrombotic stroke model to study circadian rhythm in awake mice

A minimally invasive thrombotic stroke model to study circadian rhythm in awake mice

Deep analysis of CD4 T cells in the rhesus CNS during SIV infection

CD4 T cell Responses in the CNS during SIV infection

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