Malignant gliomas are lethal brain tumors characterized by profound local immunosuppression and a radically remodeled myeloid landscape. Although these tumors mobilize resident microglia and infiltrating monocyte-derived macrophages, the mechanisms governing their phenotypic convergence and diversification remain elusive. Here, we integrated single-cell profiling and spatial transcriptomics of glioma-associated microglia in the GL261 model. We identified distinct microglial states that aligned with tumor architecture, most notably Cst7-expressing disease-associated microglia (DAMs) that aggregated at the tumor invasive margin and exhibited a conserved transcriptional signature shared across various central nervous system pathologies. Interferon-γ and toll-like receptor signaling sequentially tuned stage-specific DAM features, including transient MHC-II expression and sustained PD-L1 upregulation, thereby recalibrating the local immune equilibrium by reshaping bidirectional DAM-T cell interactions during glioma progression. Our findings highlight microglial state transitions as a stage-specific layer of immune regulation in glioma that shapes T cell fate and support targeting microglial plasticity to rebalance anti-tumor immunity.
Jiawen Qian, Chen Wang, Yi Zhang et al.· Immunity· 0 citations
Neurological and neuropsychiatric symptoms, collectively termed neuroPASC, are among the most prevalent Post-Acute Sequelae of COVID-19 (PASC). Neuroinflammation – particularly microglia reactivity – has been implicated in neuroPASC. We previously established a PASC model in which SARS-CoV-2-infected mice developed persistent behavior alterations and prolonged neuroinflammation for up to 120 days post-infection (dpi). Here, we extend these results to a longitudinal single-cell RNA sequencing analysis of brain immune cells collected at 0, 6, 30, and 100 dpi. We identify a coordinated contribution of infiltrating and resident myeloid cells to the initiation and persistence of neuroinflammation. In specific, microglia display sustained expansion of subclusters characterized by inflammatory, stress response, and metabolic signatures. Border-associated macrophages upregulate monocyte attractants during acute infection. Concurrently, peripherally derived monocytes and neutrophils mount transient inflammatory responses, potentially triggering long-term microglial reactivity. Together, these findings provide a high-resolution atlas of brain myeloid immune dynamics during neuroPASC and highlight a central role for microglia in sustaining chronic neuroinflammation. While prolonged neuroinflammation is considered a hallmark of Post Acute Sequelae of COVID-19 (PASC), its basis is poorly understood. The authors here manifest infiltration of peripheral myeloid cells during acute infection and prolonged microglial activation in mice with PASC, potentially contributing to neurological abnormalities.
Lu Tan, A. Verma, Shearon A. Lowery et al.· Nature Communications· 0 citations
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