Joseph B. El Khoury, M.D.

Regulation of macrophage functions by Scavenger Receptors

Important functions of macrophages include binding to abnormal proteins and particles in their environment and ultimately clearing them by phagocytosis. My work focuses on characterizing the role of scavenger receptors (SR) in these important macrophage functions. We were first to report that SR bind two abnormal proteins deposited extra-cellularly. These proteins are: (a) Glucose-modified proteins found in diabetes and atherosclerosis (1). (b) Fibrillar b-amyloid peptides found in Alzheimer’s disease (2). Because the size of these particles is at times larger that the macrophages, these cells fail to engulf these abnormal proteins and remain adherent to them in a phenomenon called frustrated phagocytosis. In contrast, when the size of the particle is small enough compared to that of macrophages, these cells engulf the abnormal particles and phagocytose them. This is the case of Gram Positive bacteria, which can also be phagocytozed by macrophage SR (3). With certain abnormal proteins like oxidized LDL and fibrillar b-amyloid peptides, different scavenger receptors play complementary roles in mediating interactions of macrophages with these abnormal proteins or particles.

Recently, my laboratory began investigating the mechanism(s) of recruitment and activation of macrophages at sites of inflammation. I have been particularly interested in studying microglia, the brain’s macrophages, because they represent a unique class of macrophages and because we know very little about their role in the pathogenesis of central nervous system disorders. Recently, we found that CD36, a Class B SR is an important microglial receptor that mediates the innate immune response to fibrillar b-amyloid and plays a key role in the recruitment and activation of microglia to sites of b-amyloid deposition in Alzheimer’s disease (4). We also found that, similar to their interactions with fibrillar b-amyloid, microglia interact with a neurotoxic prion protein in vitro via their SR, and that these receptors may play significant roles in microglial-induced neurotoxicity in prion diseases. We are currently expanding these investigations using a mouse model of prion diseases and post-mortem human brain tissues from patients with prion diseases, available through the large brain bank at Harvard.

In addition to characterizing the role of known SR in macrophage biology, we have recently cloned a novel macrophage SR termed SR-F1. We are in the process of characterizing the role of this receptor in several macrophage functions including phagocytosis and adhesion.

References:

1. J. El Khoury, C. A. Thomas, J. D. Loike, S. E. Hickman, L. Cao, and S.C. Silverstein. Macrophages adhere to glucose-modified basement membrane collagen IV via their scavenger receptors. J. Biol. Chem. 1994, 269:14, 10197-10200

2. J. El Khoury, S.E. Hickman, C.A. Thomas, L. Cao, S.C. Silverstein, and J.D. Loike. Scavenger receptor-mediated adhesion of microglia to β-amyloid fibrils. Nature 1996, 382:716-719.

3. C.A. Thomas, Tatsuhiko Kodama, Hiroshi Suzuki, S.C. Silverstein, and J. EL Khoury. Protection from lethal gram positive infection by scavenger receptor mediated phagocytosis J. Exp. Med 2000, 191:147-156.

4. J. El Khoury, Moore K. J., Terada K., Means T., Leung J., Toft M., Freeman M. and Luster A.D. A CD36 mediated innate host response to Beta Amyloid. J. Exp. Med. 2003, 197:1657-1666.


	Joseph B. El Khoury, M.D. Regulation of macrophage functions by Scavenger Receptors Important functions of macrophages include binding to abnormal proteins and particles in their environment and ultimately clearing them by phagocytosis. My work focuses on characterizing the role of scavenger receptors (SR) in these important macrophage functions. We were first to report that SR bind two abnormal proteins deposited extra-cellularly. These proteins are: (a) Glucose-modified proteins found in diabetes and atherosclerosis (1). (b) Fibrillar b-amyloid peptides found in Alzheimer’s disease (2). Because the size of these particles is at times larger that the macrophages, these cells fail to engulf these abnormal proteins and remain adherent to them in a phenomenon called frustrated phagocytosis. In contrast, when the size of the particle is small enough compared to that of macrophages, these cells engulf the abnormal particles and phagocytose them. This is the case of Gram Positive bacteria, which can also be phagocytozed by macrophage SR (3). With certain abnormal proteins like oxidized LDL and fibrillar b-amyloid peptides, different scavenger receptors play complementary roles in mediating interactions of macrophages with these abnormal proteins or particles. Recently, my laboratory began investigating the mechanism(s) of recruitment and activation of macrophages at sites of inflammation. I have been particularly interested in studying microglia, the brain’s macrophages, because they represent a unique class of macrophages and because we know very little about their role in the pathogenesis of central nervous system disorders. Recently, we found that CD36, a Class B SR is an important microglial receptor that mediates the innate immune response to fibrillar b-amyloid and plays a key role in the recruitment and activation of microglia to sites of b-amyloid deposition in Alzheimer’s disease (4). We also found that, similar to their interactions with fibrillar b-amyloid, microglia interact with a neurotoxic prion protein in vitro via their SR, and that these receptors may play significant roles in microglial-induced neurotoxicity in prion diseases. We are currently expanding these investigations using a mouse model of prion diseases and post-mortem human brain tissues from patients with prion diseases, available through the large brain bank at Harvard. In addition to characterizing the role of known SR in macrophage biology, we have recently cloned a novel macrophage SR termed SR-F1. We are in the process of characterizing the role of this receptor in several macrophage functions including phagocytosis and adhesion. References: 1. J. El Khoury, C. A. Thomas, J. D. Loike, S. E. Hickman, L. Cao, and S.C. Silverstein. Macrophages adhere to glucose-modified basement membrane collagen IV via their scavenger receptors. J. Biol. Chem. 1994, 269:14, 10197-10200 2. J. El Khoury, S.E. Hickman, C.A. Thomas, L. Cao, S.C. Silverstein, and J.D. Loike. Scavenger receptor-mediated adhesion of microglia to β-amyloid fibrils. Nature 1996, 382:716-719. 3. C.A. Thomas, Tatsuhiko Kodama, Hiroshi Suzuki, S.C. Silverstein, and J. EL Khoury. Protection from lethal gram positive infection by scavenger receptor mediated phagocytosis J. Exp. Med 2000, 191:147-156. 4. J. El Khoury, Moore K. J., Terada K., Means T., Leung J., Toft M., Freeman M. and Luster A.D. A CD36 mediated innate host response to Beta Amyloid. J. Exp. Med. 2003, 197:1657-1666.