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  • 1
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    Online Resource
    Abstract TP239: Cholesterol And LXR Signaling In The Macrophage Response To Intracerebral Hemorrhage-relevant Stimulation
    Ovid Technologies (Wolters Kluwer Health) ; 2022
    In:  Stroke Vol. 53, No. Suppl_1 ( 2022-02)
    Details
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 53, No. Suppl_1 ( 2022-02)
    Abstract: Introduction: In the acute phase of intracerebral hemorrhage (ICH), blood-derived macrophages contribute to an inflammatory response that increases neuronal death and worsens patient outcome. A better understanding of the endogenous signals that control this response would aid in development of therapeutics to suppress it. Uptake of free cholesterol limits the macrophage response to microbial ligands, in part through activation of the transcription factor LXR. During ICH, blood-derived macrophages in the hematoma are not exposed to microbes but are exposed to the endogenous inflammatory molecule S100A9 as well as cholesterol in the form of myelin and cell debris. Methods and Results: Murine bone marrow-derived macrophages were treated with cholesterol before stimulation with S100A9 or LPS, which are both TLR4 ligands. The inflammatory response was measured by production of the cytokines/chemokines TNF, IL-6, CCL2, and IL-10 by multiplex ELISA and/or qPCR at 3 and 6 hours after stimulation. Activation of LXR was measured by expression of the LXR target genes Abca1 and Abcg1 by qPCR. Cholesterol limited inflammatory cytokine production in response to LPS but not to S100A9. Treatment with the LXR agonist T0901317 activated Abca1 and Abcg1 more strongly than cholesterol but was not as effective at suppressing cytokine production. Treatment with the LXR antagonist GSK2033 suppressed cholesterol-mediated expression of Abca1 and Abcg1 but did not block all suppressive effects of cholesterol on cytokine production. Conclusions: Cholesterol limits the macrophage response to LPS. This is partially through activation of LXR, but LXR-independent mechanisms are involved as well. Cholesterol does not limit the initial inflammatory response to the ICH-relevant molecule S100A9, which may help explain the robust acute inflammatory response that develops during acute ICH in the presence of abundant cholesterol.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    URL: Article
    DOI: 10.1161/str.53.suppl_1.TP239
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2022
    detail.hit.zdb_id: 1467823-8
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  • 2
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    Abstract 178: Cholesterol Limits Macrophage Activation in Response to Intracerebral Hemorrhage-Relevant Signals
    Ovid Technologies (Wolters Kluwer Health) ; 2020
    In:  Stroke Vol. 51, No. Suppl_1 ( 2020-02)
    Details
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 51, No. Suppl_1 ( 2020-02)
    Abstract: Introduction: In response to intracerebral hemorrhage (ICH), monocytes are recruited to the brain parenchyma, where they differentiate into macrophages and contribute to a pathological inflammatory response. However, by day 3 after ICH, brain macrophages have adopted a more reparative phenotype and are important for clearance of apoptotic cells and recovery. The signals that control this inflammatory to reparative differentiation are incompletely understood, but cholesterol has been found to limit macrophage activation in multiple systems. The brain has the highest cholesterol content of any organ and we hypothesized that cholesterol uptake by macrophages limits inflammation and promotes the development of reparative macrophages following ICH. Methods and Results: Murine bone marrow-derived macrophages were stimulated with a cocktail of thrombin, S100A8, and IL-1b in order to mimic the Danger-Associated Molecular Patterns present in the brain after ICH (ICH-DAMP), LPS, or vehicle for 14-18 hours. Cytokine production was quantified by cytometric bead array and activation markers by flow cytometry. ICH-DAMP was found to upregulate CCL2, IL-6 and TNF, recapitulating the inflammatory phenotype seen in the first days after ICH. However, when cells were stimulated in the presence of cholesterol, production of CCL2, IL-6, and TNF were limited. Dectin-1 has inhibitory properties in some sterile injury models. ICH-DAMP was found to limit expression of dectin-1, and cholesterol reversed this inhibition. Exposure to exogenous cholesterol also upregulated the cholesterol transporter ABCA1, allowing cells to efflux excess cholesterol. The drug Valspodar was therefore used to block cholesterol efflux and was found to further limit ICH-DAMP-mediated upregulation of CCL2. Conclusion: These results suggest that the cholesterol in the brain may limit macrophage activation in response to the stimuli present during intracerebral hemorrhage.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    URL: Article
    DOI: 10.1161/str.51.suppl_1.178
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2020
    detail.hit.zdb_id: 1467823-8
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  • 3
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    Cholesterol, LXR activation, and myelin uptake in the macrophage response to diverse signals
    The American Association of Immunologists ; 2022
    In:  The Journal of Immunology Vol. 208, No. 1_Supplement ( 2022-05-01), p. 111.23-111.23
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 208, No. 1_Supplement ( 2022-05-01), p. 111.23-111.23
    Abstract: Monocyte-derived macrophages contribute to neurotoxic inflammation during hemorrhagic stroke. Cholesterol is an immunosuppressive molecule present at high levels in the brain, primarily as a component of myelin. Uptake of myelin and activation of the transcription factor LXR downstream of myelin and cholesterol uptake limits the macrophage response to LPS. However, the roles of these molecules in macrophage responses to the endogenous signals present during sterile inflammation are poorly understood. The present study seeks to determine what role myelin, cholesterol, and LXR activation play in modifying macrophage responses to diverse signals. Methods and Results Murine bone marrow-derived macrophages were treated with myelin, cholesterol, or the LXR agonist T0901317 18h before stimulation with S100A9, IFN-g, TNF-a, IL-4, IL-10, TGF-b, p(I:C), Pam3CSK4, or LPS. Production of TNF-a, IL-6, CCL2, and IL-10 were measured by multiplex ELISA. Transcriptome-wide effects were measured by RNA sequencing. Cholesterol limited inflammatory cytokine production in response to LPS but not to other stimuli. The LXR agonist T0901317 did not suppress cytokine production. Principal component analysis revealed that cholesterol had strong effects on the transcriptomic responses to LPS but not to the other stimulations. Myelin affected the transcriptomic response to all inflammatory stimulations. Conclusions Cholesterol limits the macrophage response to LPS, partially through activation of LXR, but does not broadly limit macrophage activation. Uptake of myelin has broader effects than cholesterol, suggesting that non-cholesterol components of myelin modulate the macrophage response. Supported by grants from NIH (R01 NS097728,  T32 HL007950) and AHA (Postdoctoral Fellowship 830877)
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.208.Supp.111.23
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2022
    detail.hit.zdb_id: 1475085-5
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  • 4
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    Anatomic segmentectomy versus lobectomy for clinical stage I non-small cell lung cancer: A propensity-matched analysis.
    American Society of Clinical Oncology (ASCO) ; 2012
    In:  Journal of Clinical Oncology Vol. 30, No. 15_suppl ( 2012-05-20), p. 7071-7071
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 30, No. 15_suppl ( 2012-05-20), p. 7071-7071
    Abstract: 7071 Background: Although anatomic segmentectomy is considered a “compromised” procedure by many surgeons, new information from several retrospective, single-institution series has countered negative premises regarding tumor recurrence and patient survival. The primary objective of this study was to utilize propensity score matching to compare outcomes following these anatomic resection approaches for stage I NSCLC. Methods: Patients undergoing lobectomy (n=392) vs. segmentectomy (n=793) for clinical stage I NSCLC were matched 1:1 using a propensity score that accounted for the potential confounding effects of pre-operative patient variables. Matching based on propensity scores produced 312 patients in each group. Primary outcome variables included recurrence-free and overall survival. Factors affecting survival were assessed by proportional hazards (Cox) regression and Kaplan-Meier survival function estimates. Results: Peri-operative mortality was 1.2% in the segmentectomy group and 2.5% in the lobectomy group (p=0.38). Ninety-day mortality was 2.6% and 4.8% (p=0.20), respectively. At a mean follow-up of 5.4 years, no differences were noted in locoregional (5.5% vs. 5.1%, p=1.00), distant (14.8% vs. 11.6%, p=0.29) or overall recurrence rates (20.2% vs. 16.7%, p=0.30) when comparing segmentectomy with lobectomy. Furthermore, no significant differences were noted in time to recurrence (p=0.415) or overall survival (p=0.258) when comparing the matched groups. Five year freedom from recurrence (95% CI) was: Segment 0.70 [95% CI: (0.63, 0.78) vs. Lobe 0.71 [95% CI: 0.64, 0.78]. Overall survival (95% CI) was: Segment 0.54 [95% CI: (0.47, 0.51) vs. Lobe 0.60 [95% CI: 0.54, 0.67] . Segmentectomy was not found to be an independent predictor of recurrence (HR: 1.11, 95% CI: 0.87, 1.40) or overall survival (HR = 1.17, 95% CI: 0.89.1.52). Conclusions: In this large propensity-matched comparison, anatomic segmentectomy is associated with similar time to recurrence and overall survival rates when compared to lobectomy for clinical stage I NSCLC. These results will need further validation by prospective, randomized trials (CALGB 140503).
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2012.30.15_suppl.7071
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2012
    detail.hit.zdb_id: 2005181-5
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  • 5
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    Online Resource
    Divergent Functions of Tissue-Resident and Blood-Derived Macrophages in the Hemorrhagic Brain
    Ovid Technologies (Wolters Kluwer Health) ; 2021
    In:  Stroke Vol. 52, No. 5 ( 2021-05), p. 1798-1808
    Details
    In: Stroke, Ovid Technologies (Wolters Kluwer Health), Vol. 52, No. 5 ( 2021-05), p. 1798-1808
    Abstract: Brain tissue-resident microglia and monocyte-derived macrophages (MDMs) are innate immune cells that contribute to the inflammatory response, phagocytosis of debris, and tissue repair after injury. We have previously reported that both microglia and MDMs transition from proinflammatory to reparative phenotypes over days after an intracerebral hemorrhage (ICH). However, their individual functional properties in the brain remain largely unknown. Here we characterized the differences between microglia and MDMs and further elucidate their distinct activation states and functional contributions to the pathophysiology and recovery after ICH. Methods: Autologous blood injection was used to model ICH in mice. Longitudinal transcriptomic analyses on isolated microglia and MDMs from mice at days 1, 3, 7 and 10 after ICH and naive controls identified core transcriptional programs that distinguish these cells. Imaging flow cytometry and in vivo phagocytosis assays were used to study phagocytic ability of microglia and MDMs. Antigen presentation was evaluated by ovalbumin-OTII CD4 T-cell proliferation assays with bone marrow–derived macrophages and primary microglia cultures. Results: MDMs had higher phagocytic activity and higher erythrophagocytosis in the ICH brain. Differential gene expression revealed distinct transcriptional signatures in the MDMs and microglia after ICH. MDMs had higher expression of MHCII (major histocompatibility complex class II) genes than microglia at all time points and greater ability to induce antigen-specific T-cell proliferation. Conclusions: The different ontogeny of microglia and MDMs lead to divergent responses and functions in the inflamed brain as these 2 cell populations differ in phagocytic functions and antigen-presenting capabilities in the brain after ICH.
    Type of Medium: Online Resource
    ISSN: 0039-2499 , 1524-4628
    URL: Article
    DOI: 10.1161/STROKEAHA.120.032196
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2021
    detail.hit.zdb_id: 1467823-8
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