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Stroke induces disease-specific myeloid cells in the brain parenchyma and pia.

ABSTRACT: Inflammation triggers secondary brain damage after stroke. The meninges and other CNS border compartments serve as invasion sites for leukocyte influx into the brain thus promoting tissue damage after stroke. However, the post-ischemic immune response of border compartments compared to brain parenchyma remains poorly characterized. Here, we deeply characterize tissue-resident leukocytes in meninges and brain parenchyma and discover that leukocytes respond differently to stroke depending on their site of residence. We thereby discover a unique phenotype of myeloid cells exclusive to the brain after stroke. These stroke-associated myeloid cells partially resemble neurodegenerative disease-associated microglia. They are mainly of resident microglial origin, partially conserved in humans and exhibit a lipid-phagocytosing phenotype. Blocking markers specific for these cells partially ameliorates stroke outcome thus providing a potential therapeutic target. The injury-response of myeloid cells in the CNS is thus compartmentalized, adjusted to the type of injury and may represent a therapeutic target.

SUBMITTER: Beuker C

PROVIDER: S-EPMC8854573 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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Stroke induces disease-specific myeloid cells in the brain parenchyma and pia.

Beuker Carolin C Schafflick David D Strecker Jan-Kolja JK Heming Michael M Li Xiaolin X Wolbert Jolien J Schmidt-Pogoda Antje A Thomas Christian C Kuhlmann Tanja T Aranda-Pardos Irene I A-Gonzalez Noelia N Kumar Praveen Ashok PA Werner Yves Y Kilic Ertugrul E Hermann Dirk M DM Wiendl Heinz H Stumm Ralf R Meyer Zu Hörste Gerd G Minnerup Jens J

Nature communications 20220217 1

Inflammation triggers secondary brain damage after stroke. The meninges and other CNS border compartments serve as invasion sites for leukocyte influx into the brain thus promoting tissue damage after stroke. However, the post-ischemic immune response of border compartments compared to brain parenchyma remains poorly characterized. Here, we deeply characterize tissue-resident leukocytes in meninges and brain parenchyma and discover that leukocytes respond differently to stroke depending on their ...[more]

PMID: 35177618

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Project description:Microglia are brain-resident myeloid cells and play a major role in the innate immune responses of the CNS and the pathogenesis of Alzheimer's disease (AD). However, the contribution of nonparenchymal or brain-infiltrated myeloid cells to disease progression remains to be demonstrated. Here, we show that monocyte-derived cells (MDC) invade brain parenchyma in advanced stages of AD continuum using transcriptional analysis and immunohistochemical characterization in post-mortem human hippocampus. Our findings demonstrated that a high proportion (60%) of demented Braak V-VI individuals was associated with up-regulation of genes rarely expressed by microglial cells and abundant in monocytes, among which stands the membrane-bound scavenger receptor for haptoglobin/hemoglobin complexes or Cd163. These Cd163-positive MDC invaded the hippocampal parenchyma, acquired a microglial-like morphology, and were located in close proximity to blood vessels. Moreover, and most interesting, these invading monocytes infiltrated the nearby amyloid plaques contributing to plaque-associated myeloid cell heterogeneity. However, in aged-matched control individuals with hippocampal amyloid pathology, no signs of MDC brain infiltration or plaque invasion were found. The previously reported microglial degeneration/dysfunction in AD hippocampus could be a key pathological factor inducing MDC recruitment. Our data suggest a clear association between MDC infiltration and endothelial activation which in turn may contribute to damage of the blood brain barrier integrity. The recruitment of monocytes could be a consequence rather than the cause of the severity of the disease. Whether monocyte infiltration is beneficial or detrimental to AD pathology remains to be fully elucidated. These findings open the opportunity to design targeted therapies, not only for microglia but also for the peripheral immune cell population to modulate amyloid pathology and provide a better understanding of the immunological mechanisms underlying the progression of AD.

Project description:BACKGROUND:Activation of transforming growth factor-?-activated kinase 1 (TAK1) occurs after stroke and leads to an exacerbation of brain injury. TAK1 is involved in innate and adaptive immune responses, but it has divergent inflammatory effects that are dependent on the cell type in which it is activated. There is a robust infiltration of myeloid cells after stroke; however, the contribution of myeloid TAK1 to cerebral ischemia is currently unknown. We hypothesized that myeloid-specific deletion of TAK1 would protect against ischemic brain injury. METHODS:Myeloid TAK1?M and wild-type (WT) mice were subjected to middle cerebral artery occlusion (MCAo). Brain-infiltrating and splenic immune cells were evaluated at 3 days after stroke. Assessment of infarct size and behavioral deficits were performed on days 3 and 7 post-stroke. RESULTS:Infarcts were significantly smaller in TAK1?M mice (p?<?0.01), and behavioral deficits were less severe despite equivalent reduction in cerebral blood flow. Flow cytometry demonstrated an increase in the frequency of splenic monocytes and neutrophils (p?<?0.05) and a decrease in splenic CD3+ T (p?<?0.01) and CD19+ B (p?=?0.06) cells in TAK1?M mice compared to WT at baseline. Three days after stroke, a significant increase in the number of brain-infiltrating immune cell was observed in both TAK1?M (p?<?0.05) and WT (p?<?0.001) mice compared to their respective shams. However, there was a significant decrease in the infiltrating CD45hi immune cell counts (p?<?0.05), with a pronounced reduction in infiltrating monocytes (p?<?0.001) in TAK1?M after stroke compared to WT stroke mice. Additionally, a significant reduction in CD49d+ monocytes was seen in the brains of TAK1?M stroke mice compared to wild-type mice. Importantly, TAK1?M MCAo mice had smaller infarcts and improved behavioral outcomes at day 7 post-stroke. CONCLUSION:Our results showed that deletion of myeloid TAK1 resulted in smaller infarcts and improved functional outcomes at the peak of inflammation (day 3) and a reduction in brain-infiltrating immune cells that were primarily monocytes. Myeloid TAK1 deletion was also protective at 7 days post MCAo, reflecting a detrimental role of myeloid TAK1 in the progression of ischemic injury.

Dataset Information

Stroke induces disease-specific myeloid cells in the brain parenchyma and pia.

Publications

Stroke induces disease-specific myeloid cells in the brain parenchyma and pia.

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