While for short RNA oligonucleotides the immunological activity is clearly sequence dependent (Hornung et al. 2005; Judge et al. 2005), for long RNA molecules such as mRNA, sequence specificity of immunological activity is less prominent (Scheel et al. 2005). This raises the question of how the immune system is able to distinguish between self and non-self (for example viral) RNA. This question was addressed recently by Kariko and colleagues (2005) who showed that human mitochondrial RNA, when transfected into monocyte-derived dendritic cells, provoked secretion of TNF-a at similar quantities compared to total RNA isolated from Escherichia coli. In contrast, RNA of other cellular compartments showed no immunological activity. The authors proposed that mammalian RNA is masked by naturally occurring nucleoside modifications that are expected to be similar in closely related species. According to this concept, mitochondrial RNA is stimulatory since it resembles bacterial rather than mammalian RNA. In healthy cells, mitochondrial RNA will not be released. In contrast to other self-RNA, mitochondrial RNA never enters the cytosolic compartment. As a consequence, mitochondrial RNA under healthy conditions is not detected by cytosolic mechanisms of detection. Only if the cell is lysed can mitochondrial RNA enter the endosomal compartment of immune cells via phagocytosis. Indeed, the stimulatory effect of in vitro RNA transcripts composed of unmodified nucleotides in their study could be abrogated by incorporation of modified nucleosides such as pseudouridine, 5-methylcytidine, N6-methyladenosine, inosine, and N7-methylguanosine. In order to examine modification sensitivity of different TLRs, HEK293 cells expressing TLR3, TLR7, TLR8, or TLR9 were transfected with RNA containing modified nucleosides. Transfection of unmodified RNAs stimulated IL-8 production (sensitive readout for immunoactivation of HEK293 cells) in HEK293 cells overexpressing TLR3, 7, and 8. Interestingly, RNA recognition by TLR3, TLR7, and TLR8 is suppressed by the presence of different types of modified nucleotides within the RNA ligand. TLR3 was the least sensitive receptor with regard to suppression by nucleoside modifications. Furthermore, the authors showed that in monocyte-derived dendritic cells, 5%-10% of modified nucleosides were sufficient to inhibit TNF-a secretion by 75%-90%. Together, these results show that RNA modification contributes to the distinction of self versus non-self RNA by the immune system.
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