IMMUNOLOGY AND INFLAMMATORY DISEASES
El Khoury Laboratory: Joseph El Khoury, MD
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Neuroimmunology and Innate Immunity Laboratory
The Laboratory of Joseph El Khoury, MD, at Massachusetts General Hospital focuses on studying the role of macrophages and microglia in neurodegeneration, host defense and inflammation. We are investigating the mechanisms by which modified-self proteins such as β-amyloid (Aβ) and non-self-infectious pathogens (Staphylococcus Aureus and Cryptococcus neoformans) interact with microglia and macrophages, how they activate these cells to produce proinflammatory molecules and how microglia and macrophages are recruited to sites of deposition of Aβ and infections.
Dr. El Khoury’s previous work showed that macrophage and microglial scavenger receptors such as SRA and CD36 promote binding of microglia and macrophages to infectious microorganisms and Aβ. We have also found that different scavenger receptors play complementary roles in mediating interactions of macrophages with these proteins and pathogens. We are currently extending these studies to determine if SRA, CD36 and various other scavenger receptors such SRF, Lox-1 and MARCO collaborate with other receptors involved in innate immunity such as Toll-like receptors, to determine the role of such interactions in mediating intracellular signaling induced by infectious microorganisms and Aβ.
In addition, we are also looking at the role of chemokines such as MCP-1 and Fractalkine, and their chemokine receptors expressed on macrophages and microglia such as CCR2 and CX3CR1 in the recruitment of these cells to sites of inflammation and infection. We have found that interactions of infectious particles or organisms and Aβ with scavenger receptors promote production of these chemokines, suggesting that the interactions of infectious pathogens and modified self proteins with scavenger receptors are involved in the recruitment of inflammatory cells to sites of infection and injury. We use mouse models for bacterial, fungal and neurodegenerative disorders to perform these studies and delineate the role of these molecules in vivo.
Scavenger Receptors and Alzheimer’s Disease
Work done previously in our laboratory showed that scavenger receptors bind to Aβ, the pathogenic peptide that accumulates in Alzheimer’s disease patients. This project focuses on determining the exact roles of various scavenger receptors in the pathogenesis of Alzheimer’s disease and the molecular and biochemical pathways initiated by interactions of Aβ with these receptors. This project involves the use of transgenic mouse models of Alzheimer’s disease, postmortem human brain tissues from Alzheimer’s patients and a wide variety of cellular, molecular and biochemical techniques.
Toll-Like Receptor Signaling in Alzheimer’s Disease
Toll like receptors are innate immune receptors that mediate host defense against infectious pathogens. Recent work from our laboratory indicates that downstream signaling events from these receptors are involved in the pathogenesis of Alzheimer’s disease. We are currently dissecting the role of these signaling pathways in the pathogenesis of Alzheimer’s disease using mouse models of this disease and a variety of cellular, molecular and biochemical techniques.
Scavenger Receptors in Fungal Pathogenesis
Recent work from our laboratory identified the scavenger receptors CD36 and SCARF1 as important macrophage receptors involved in host defense against the pathogenic yeast Cryptococcus neoformans. This project focuses on studying the role of these receptors in pulmonary and CNS infections with C. neoformans.
Generation of a Comprehensive Panel of Reagents for the Study of Scavenger Receptors
Our laboratory is spearheading a major project to generate a comprehensive panel of reagents to study scavenger receptors. We are in the process of generating monoclonal antibodies, recombinant soluble proteins, stable cell lines, knockout cell lines and knockout mice for known scavenger receptors. Once generated, these reagents will be made available to the research community.
Mechanism of Mononuclear Phagocyte Accumulation in Alzheimer’s Disease
Recent work from our laboratory identified the chemokine receptor CCR2 as an important receptor regulating the early accumulation of mononuclear phagocytes in Alzheimer’s mouse models. This project focuses on understanding the role of various chemokine receptors in this process.
Joseph El Khoury, MD
Principal Investigator, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital
Associate Physician, Infectious Disease Unit, Massachusetts General Hospital
Associate Professor of Medicine, Harvard Medical School
Suzanne Hickman, PhD
Saef Izzy, MD
Pritha Sen, MD
Taotao Lao, PhD
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Our faculty at the Center for Immunology and Inflammatory Diseases at Massachusetts General Hospital leads an aggressive multi-pronged effort to unlock the mysteries of immune and inflammatory diseases and to translate findings into improved clinical care as soon as possible.