Epub: Han et al. Janus-like opposing roles of CD47 in autoimmune brain inflammation in humans and mice. J Exp Med. 2012 Jun 25.
Comparison of transcriptomic and proteomic data from pathologically similar multiple sclerosis (MS) lesions reveals down-regulation of CD47 at the messenger RNA level and low abundance at the protein level. Immunohistochemical studies demonstrate that CD47 is expressed in normal myelin and in foamy macrophages and reactive astrocytes within active MS lesions. We demonstrate that CD47(-/-) mice are refractory to experimental autoimmune encephalomyelitis (EAE), primarily as the result of failure of immune cell activation after immunization with myelin antigen. In contrast, blocking with a monoclonal antibody against CD47 in mice at the peak of paralysis worsens EAE severity and enhances immune activation in the peripheral immune system. In vitro assays demonstrate that blocking CD47 also promotes phagocytosis of myelin and that this effect is dependent on signal regulatory protein α (SIRP-α). Immune regulation and phagocytosis are mechanisms for CD47 signaling in autoimmune neuroinflammation. Depending on the cell type, location, and disease stage, CD47 has Janus-like roles, with opposing effects on EAE pathogenesis.
CD47 is a membrane protein, which is involved in the increase in intracellular calcium concentration that occurs upon cell adhesion to extracellular matrix. The protein is also a receptor for the C-terminal cell binding domain of thrombospondin, and it may play a role in membrane transport and signal transduction. Mice that CD47 do not get MS-like disease (EAE) which suggests that it may be involved in the generation of immune responses. Targeting of CD47 with an antibody however appears to make the MS-like disease worse. Blocking of CD47 prevents scavanging by macrophages and this inhibits scavaging of myelin. This is likely to block repair. Therefore this is unlikely to be a useful target for changing the course of MS. This type of Janus -like effect is common to a number of etargets that could be useful yet could be harmful. This is because biology harnesses what it makes to produce different effects depending on context to which it is is activated. This is why drugs can often have unwanted side effects. Many of the the targets that are been found to stimulate remyleination could have other functions elsewhere.