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Blocking Action of a Macrophage Surface Protein Limits Damage in Chronic Inflammatory Diseases

By BiotechDaily International staff writers
Posted on 18 Jul 2013
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Image: Predicted topology of CD36 in the plasma membrane (Photo courtesy of Wikimedia Commons).
Image: Predicted topology of CD36 in the plasma membrane (Photo courtesy of Wikimedia Commons).
The macrophage integral membrane protein CD36 (Cluster of Differentiation 36) has been identified as a central regulator of inflammasome activation in several chronic inflammatory disease such as atherosclerosis, Alzheimer's disease, and diabetes.

The inflammasome is a multiprotein oligomer consisting of caspase 1, PYCARD, NALP, and sometimes caspase 5. It is expressed in myeloid cells and is a component of the innate immune system. The exact composition of an inflammasome depends on the activator that initiates its assembly. For example, dsRNA will trigger one inflammasome composition while asbestos will assemble a different variant. An inflammasome promotes the maturation of inflammatory cytokines interleukin 1-beta (IL-1-beta) and interleukin 18 (IL-18). The inflammasome is responsible for activation of inflammatory processes and has been shown to induce cell pyroptosis, a process of programmed cell death distinct from apoptosis.

CD36 is a member of the class B scavenger receptor family of cell surface proteins. As such, it binds many ligands including collagen, thrombospondin, erythrocytes infected with the malaria parasite Plasmodium falciparum, oxidized low-density lipoprotein (LDL), native lipoproteins, oxidized phospholipids, and long-chain fatty acids. It was thought that CD36 mediated removal of particulate inflammatory ligands such as amyloid plaques or cholesterol crystals.

A paper published in the June 30, 2013, online edition of the journal Nature Immunology better defined the role of CD36 in the inflammatory process. Investigators at the New York University Langone Medical Center (NY, USA) reported that CD36 coordinated the immune response to soluble endogenous ligands, including oxidized LDL, and amyloid-beta and amylin peptides that accumulate in various chronic inflammatory diseases. They identified an endocytic pathway mediated by the pattern-recognition receptor conversion of those soluble ligands into crystals or fibrils, which resulted in lysosomal disruption and activation of the NLRP3 inflammasome. Consequently, macrophages that lacked CD36 failed to elicit IL-1-beta production in response to those ligands, and targeting CD36 in atherosclerotic mice resulted in lower serum concentrations of IL-1-beta and accumulation of fewer cholesterol crystals into atherosclerotic plaques.

“Our findings identify CD36 as a central regulator of the immune response in these conditions and suggest that blocking CD36 might be a common therapeutic option for all three diseases,” said senior author Dr. Kathryn J. Moore, associate professor of medicine and cell biology, at the New York University Langone Medical Center.

“What we found is that CD36 binds soluble cholesterol and protein matter associated with these diseases, pulls them inside the cell, and then transforms them. The resulting insoluble crystals and amyloid damage the macrophage and trigger a powerful cytokine, called interleukin-1-beta, linked to a chronic inflammatory response.”

Related Links:
New York University Langone Medical Center

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