Global large-scale comparisons of protein and RNA profile had previously been investigated in experimental systems (Kislinger et al., 2006
; Wu et al., 2007
). To our knowledge, systematic integration of multiple platforms has never been reported in a study of MS. This study used two different platforms for “-omic” analysis and provided quantitative expression patterns of genes and proteins from the same MS brain lesions. This exercise illustrated dynamic changes in mRNA and protein expression profiles. It revealed differences in outcomes for transcriptomic and proteomic platforms. It also selected targets that were confluent with both platforms and instigated interest to perform in depth studies of molecules such as CD47. Although there were many other targets that showed concordant changes on transcriptional and proteomic platforms, we selected CD47, one of the intriguing molecules in the set, to exemplify how such large-scale profiles could shed mechanistic insights into pathophysiology. The identification of key molecules with these large-scale technological platforms covering proteins and gene transcripts was merely the first major step in understanding function.
The discordant and opposing effects of CD47 on peripheral immune cells and the CNS raised several intriguing points on the biology of CD47. Here we showed there was increased phagocytosis of myelin in the CNS when CD47 was down-regulated. However, this finding does not explain why there is peripheral immune activation in the anti-CD47–treated EAE mice (). One other explanation, not necessarily mutually exclusive, is that continued presentation of antigen (myelin peptide MOG) by APCs might worsen disease severity.
CD47 is ubiquitously expressed in all resident cells of the CNS, but its exact function in neurons, astrocytes, and myelin has not been examined (Cahoy et al., 2008
). The novel finding of CD47 in association with compact myelin also raised several possibilities on how it might play a role in demyelinating disease. CD47, also known as integrin-associated protein might well be involved in packing the myelin sheath around axons. Whether lack of CD47 promotes demyelination in vivo by SIRP-α–dependent phagocytosis has not been investigated. Furthermore, whether removal of myelin debris is detrimental or promotes new myelin formation also remains to be answered. These important questions are currently being addressed in our laboratory by using tools such as CD47−/−
mice in lysolecithin-induced demyelination.
Astrocytes play a crucial role in MS pathogenesis by modulating inflammation and maintaining the integrity of the blood–brain barrier and repair of demyelinating lesions (Barres, 2008
). Junker et al. (2009)
, as well as our own experiments, suggested that reactive astrocytes in active MS lesions (and not on astrocytes in chronic MS lesions) express high levels of CD47. Findings from our immunohistochemical experiments of MS lesions are also in agreement with their findings, suggesting that CD47 in astrocytes participates in pathogenesis of autoimmune neuroinflammation.
These experiments exemplify the dual and contradictory effects of CD47 during initiation and progression of autoimmune neuroinflammation. These Janus-like opposite findings are likely caused by expression of CD47 in different cell types. Combined with the multiple signaling pathways in which CD47 is involved, we have exposed very different roles for this molecule in different contexts. We are learning this lesson repeatedly when comparing the roles of molecules like the major histocompatibility complex and complement pathway in the immune system versus the nervous system (Stevens et al., 2007
; Shatz, 2009
). Furthermore, we are now learning that molecules well known to the nervous system like the synaptic transmitter gamma amino butyric acid play different roles in the immune system (Bhat et al., 2010
). We focused our study here on CD47–SIRP-α interactions, but other effects on inflammation may be related to CD47-Thrombospondin signaling (Lamy et al., 2007
). Future studies will focus on dissecting the interplay of these pathways to study inflammatory demyelinating diseases.
This raises an important question on whether modulating CD47 has a potential role for therapy in MS. Using blocking antibody against CD47 has been shown to be beneficial in a subset of acute myeloid leukemias (Majeti et al., 2009
). However, in a setting like autoimmune neuroinflammation where CD47 has opposing effects during early and late stages of disease, it would be important to decide whether blocking or replenishing CD47 may have different effects depending on disease stage. As a precedent, we should remember that immune therapies such as TNF blockade are beneficial in rheumatoid arthritis, whereas they worsen MS. Like many key players that maintain health and disease, modulating CD47 could at once be harmful and beneficial, depending on the context.