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Hematoma-infiltrating Macrophages Transition from Inflammatory to Reparative Programs in Intracerebral Hemorrhage Patients

Thursday, June 15
5:45 PM - 7:00 PM

Intracerebral hemorrhage (ICH) is a devastating form of acute stroke accounting for greater than half of stroke-related deaths. Circulating leukocytes are rapidly recruited to the hemorrhage; however, their role in disease progression and tissue 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 disease 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 five-day period, in conjunction with an ongoing trial for surgical evacuation of ICH. We have found that the hematoma immune infiltrate is predominantly composed of neutrophils and monocyte-derived macrophages, rather than CNS-resident microglia. We have observed that hematoma macrophages acquire a distinct phenotype from peripheral blood monocytes, suggesting that their gene expression is strongly influenced 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. 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. These findings suggest that recruited macrophages may contribute not only to initial inflammatory damage after ICH, but also to clearance of the hematoma and resolution of inflammation, making them a potentially ideal target for therapeutic intervention.

Michael H. Askenase

Postdoctoral Associate
Department of Neurology, Yale School of Medicine

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    Brittany A. Goods

    Department of Biological Engineering, Koch Institute for Integrative Cancer Research at MIT

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      Arthur F. Steinschneider

      Department of Neurology, Yale School of Medicine

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        Margaret J. Landreneau

        Department of Neurology, Yale School of Medicine

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          Hannah Beatty

          University of Connecticut

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            Khadir Raddassi

            Department of Neurology, Yale School of Medicine

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              David Hafler

              William S. and Lois Stiles Edgerly Professor of Neurology and Immunobiology Chairman, Department of Neurology
              Yale School of Medicine

              Hafler is the William S. and Lois Stiles Edgerly Professor and Chairman Department of Neurology and Professor or Immunobiology, Yale School of Medicine, and is the Neurologist-in-Chief of the Yale-New Haven Hospital. He graduated in 1974 from Emory University , and the University of Miami School of Medicine in 1978. He then completed his internship at Hopkins followed by a neurology residency at Cornell Medical Cente. Dr. Hafler was trained in immunology at the Rockefeller University and then at Harvard where he joined the faculty in 1984 and later became the Breakstone Professorship of Neurology at Harvard and was a founding Associated Member of the Broad Institute at MIT. In 2009 he moved to Yale as the Chair of the Department of Neurology. Dr. Hafler is a clinical scientist with a research interest in the mechanism of MS with over 370 publications in the field of MS, and autoimmunity. He is a co-founder of the International MS Genetic Consortium a group that identified the genes causing MS. Dr. Hafler has bee elected to membership in the American Society of Clinical Investigation, AOA, and was a Weaver Scholar of the NMSS. He is a member of the editorial boards for JCI and the JEM, and is co-founder of FOCISs. Hafler was a Javits Merit Award Recipient from the NIH and has won many awards including 2010 Dystel Prize for MS research from the AAN, the Adams Prize in 2015 from the American Neurologic Association and the 2016 Frontier Lecturer at the AAN.

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                J. Christopher Love

                Department of Chemical Engineering, Koch Institute for Integrative Cancer Research at MIT

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                  Lauren Sansing

                  Department of Neurology, Yale School of Medicine

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