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  • 1
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    Online Resource
    Abstract WMP105: Human Monocyte Derived Macrophage Phagocytize Eryptotic Erythrocytes in a Phosphotidylserine Dependent Mechanism
    Ovid Technologies (Wolters Kluwer Health) ; 2017
    In:  Stroke Vol. 48, No. suppl_1 ( 2017-02)
    Details
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 48, No. suppl_1 ( 2017-02)
    Abstract: Introduction: After intracerebral hemorrhage (ICH), erythrocytes contribute to secondary injury by releasing toxic hemoproteins. Our lab has previously shown that blood derived macrophages play an important role in ICH clearance but mechanisms of phagocytosis by human macrophages are unknown. This study aims to quantify eryptotic (phosphatidylserine (PtdSer)-expressing) red blood cells (RBCs) in an in vivo model of ICH, and to investigate the mechanisms that play a role in autologous eryptotic phagocytosis by human monocyte derived macrophages (huMDMs). Methods: ICH was induced in mice by autologous blood injection. The mice were sacrificed at 1 day after ICH. The brains were separated into hemispheres and digested into a single cell suspension for analysis by flow cytometry. Cells were stained with antibodies to cell surface markers and annexin V to quantify externalized PtdSer expression. Human monocytes were cultured with M-CSF for 7 days to generate huMDMs. Autologous RBCs were heat shocked (HS) to induce eryptosis. The huMDMs were cocultured with HS RBCs, HS RBCs treated with annexin V, or control RBCs. After 1 hour of coculture, the huMDMs were washed, stained and erythrophagocytosis quantified by microscopy. Results: The proportion of cells that externalized PtdSer increased by almost 20 fold at day 1 after ICH. Control brains mixed with fresh RBCs and subjected to tissue prep did not show PtdSer expression, ensuring that the PtdSer expression detected was induced in vivo (Fig A). HS RBCs increased PtdSer expression and were efficiently phagocytosed by huMDMs. Treatment of HS RBCs with annexin V to antagonize PtdSer-receptor interactions decreased RBC phagocytosis to levels comparable to control RBCs (Figs B and C). Conclusions: In vivo after ICH, erythrocytes externalize PtdSer, a cue to be engulfed by macrophages. Human macrophages phagocytose RBCs in a PtdSer-dependent mechanism. These findings highlight potential targets to enhance ICH clearance.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    URL: Article
    DOI: 10.1161/str.48.suppl_1.wmp105
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2017
    detail.hit.zdb_id: 1467823-8
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  • 2
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    Online Resource
    Abstract 213: Hematoma-infiltrating Macrophages Transition From Inflammatory to Reparative Programs in Patients After Intracerebral Hemorrhage
    Ovid Technologies (Wolters Kluwer Health) ; 2017
    In:  Stroke Vol. 48, No. suppl_1 ( 2017-02)
    Details
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 48, No. suppl_1 ( 2017-02)
    Abstract: Intracerebral hemorrhage (ICH) causes rapid recruitment of circulating leukocytes to the injury; however, the roles of these cells in disease progression and repair in the brain are poorly understood. Findings from animal models have failed to translate into effective therapies for ICH, emphasizing the importance of studying the ICH immune response in the patient population. To gain insight into the inflammatory response in patient hematomas, we are utilizing mass cytometry, flow cytometry, and RNA-seq to characterize hematoma-infiltrating leukocytes isolated from ICH patients over a 5 day period, in conjunction with the ongoing MISTIE III trial for surgical evacuation of ICH. We have found that the hematoma immune infiltrate is predominantly composed of neutrophils and macrophages recruited from the circulation, rather than CNS-resident microglia. We have observed that hematoma macrophages have acquired a distinct phenotype differing from phagocyte populations in the peripheral blood, suggesting that their gene expression is controlled by local signals in the hematoma. Preliminary transcriptional analysis of hematoma macrophages 24-50 hours post-ICH has revealed an inflammatory profile characterized by increased expression of antigen presentation, TLR signaling, glycolytic metabolism, and prostaglandin production pathways (Figure 1). Intriguingly, by 100 hours post-ICH, macrophages downregulated these pathways and engaged a wound healing program characterized by TGF-beta signaling, fatty acid metabolism, and collagen deposition (Figure 1). These findings, in agreement with our previous results in animal models of ICH, suggest that recruited macrophages may contribute not only to initial inflammatory damage, but also to clearance of the hematoma and resolution of inflammation, making them potentially ideal targets for therapeutic intervention.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    URL: Article
    DOI: 10.1161/str.48.suppl_1.213
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2017
    detail.hit.zdb_id: 1467823-8
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  • 3
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    Online Resource
    Abstract TP331: Plasma IL-6 Levels are Independently Associated With Functional Outcome and Markers of Secondary Injury in Spontaneous Intracerebral Hemorrhage
    Ovid Technologies (Wolters Kluwer Health) ; 2018
    In:  Stroke Vol. 49, No. Suppl_1 ( 2018-01-22)
    Details
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 49, No. Suppl_1 ( 2018-01-22)
    Abstract: Introduction: The impact of the inflammatory response after intracerebral hemorrhage (ICH) has not been well characterized in patients and little is known about the relationship between early markers of inflammation and functional outcome. It is hypothesized that cytokine levels may be associated with three-month functional outcome and radiologic markers of secondary injury. Methods: Fifty-four patients with spontaneous ICH were prospectively enrolled at Yale-New Haven Hospital. Blood samples were collected at 24 (n=44) and 72 (n = 33) hours post-ICH. Plasma cytokine levels were measured using commercially available multiplex ELISA kits (Millipore). Modified Rankin Scale (mRS) was collected at three months by telephone interview. Associations between cytokines and outcome were assessed using ordinal logistics regression. Linear regression was used to evaluate the association between cytokine levels and markers of secondary injury. Results: IL-6 was correlated with ICH volume (p = 0.003) and PHE volume (p = 0.009) in univariable analysis. In multivariable analysis, IL-6 was associated with midline shift after adjustment for ICH volume (p=0.027). 24h IL-6 (p 〈 0.001), IL-10 (p 〈 0.001), IL-15 (p = 0.001), admission Glasgow Coma Score (GCS), ICH volume, ICH Score, and external ventricular drain (EVD) placement were associated with higher (worse) mRS in univariable ordinal regression. After adjustment for the ICH score, 24h IL-6 (OR 2.00, 95% CI 1.2-3.3, p = 0.003) and IL-15 (OR 2.7, 95% CI 1.4-5.0, p = 0.007) were significantly associated with worse mRS. Conclusions: Plasma IL-6 is independently associated with 24h midline shift, a measure of global hemispheric swelling, and with functional outcome after spontaneous ICH. These data are consistent with the early robust increase in brain IL-6 in experimental models of ICH. These data warrant further investigation of IL-6 levels as a biomarker for secondary injury and poor outcome in ICH.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    URL: Article
    DOI: 10.1161/str.49.suppl_1.TP331
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2018
    detail.hit.zdb_id: 1467823-8
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  • 4
    Online Resource
    Online Resource
    Abstract TP351: Axl/Mer Receptor Tyrosine Kinase Mediates Erythrophagocytosis-Induced Macrophage Reparative Phenotype and Brain Recovery in Experimental Intracerebral Hemorrhage
    Ovid Technologies (Wolters Kluwer Health) ; 2017
    In:  Stroke Vol. 48, No. suppl_1 ( 2017-02)
    Details
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 48, No. suppl_1 ( 2017-02)
    Abstract: Introduction: Local inflammation contributes to both brain injury and recovery after intracerebral hemorrhage (ICH). Our previous studies have shown brain-infiltrating macrophages (BIMs) aggravate early brain injury after ICH; however, BIMs increase scavenger receptor CD36 levels over time, and hematoma clearance is delayed in the absence of BIMs. The mechanism that mediates BIMs phenotypic change in the ICH brain is elusive. In this study, we delineate the dynamic transcriptome profile of BIMs after ICH and test potential mediator that might modulate BIMs polarity in ICH. Methods: Autologous blood injection ICH model and thrombin-treated bone marrow-derived macrophages (BMDM) were used to mimic ICH in vivo and in vitro . BIMs were isolated by FACS, and the 780 transcriptome of BIMs were determined using NanoString. Flow cytometry and RT-qPCR were performed to detect the frequency of phosphatidylserine-positive (eryptotic) RBCs and to assess BIMs phenotype in the perihematomal tissue. Erythrophagocytosis of eryptotic RBCs was identified by immunofluorescence and microscopy. Neurologic deficit was evaluated by cylinder test. Axl/Mer receptor tyrosine kinase double knockout (AM DKO) mice, AM DKO bone-marrow chimeras, and AM DKO BMDM were used to evaluate the function of Axl/Mer on macrophage phenotype and on brain recovery after ICH. Results: BIMs highly expressed proinflammatory transcripts such as cd86 , tlr2 , nlrp3 , and tnf at days 1 and 3 post-ICH; these were decreased at days 7 and 10. Transcripts relevant to efferocytosis ( axl ) and lysosome formation ( cd63 ) increased from days 3 to 10 post-ICH. At days 1 and 3, phosphatidylserine levels was increased on RBCs in the ICH brain. Engulfment of eryptotic RBCs reduced proinflammatory phenotype of BMDM. Thrombin-stimulated AM DKO BMDM had reduced erythrophagocytosis ability and increased tnf and il-6 gene expression. AM DKO mice and AM DKO chimeras had low CD36 and high MHC II levels on BIMs and had worse functional outcome after ICH. Conclusions: BIMs initially express proinflammatory phenotype and then switch to a reparative phenotype after ICH. Axl/Mer is involved in regulation of macrophage polarity through modulating erythrophagocytosis ability and contributes to ICH brain recovery.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    URL: Article
    DOI: 10.1161/str.48.suppl_1.tp351
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2017
    detail.hit.zdb_id: 1467823-8
    Location Call Number Limitation Availability
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    Online Resource
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