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As the authors themselves therefore state, this study has serendipitously found a role for innate immune signaling in nuclear reprogramming leading to the induction of pluripotent stem cells from somatic cells. TLR3 plays an important role in the recognition of double-stranded RNA from retroviruses and activates a signaling pathway culminating in the induction of a wide range of antiviral proteins (Onder et al., 2012). Epigenetic modification of chromatin by TLRs has been reported before (Medzhitov and Horng, 2009) and is presumably important for the increase in expression of host defense genes during infection. Here, however, this epigenetic response is being deployed to allow for nuclear reprogramming by OSKM in a manner potentially safer than one using retrovirally encoded proteins. It is likely that other innate immune receptors will have a similar effect. Because the adaptor Trif is shown to be involved, it is possible that TLR4, which senses lipopolysaccharides (LPS) from gram negative bacteria and also signals via Trif (Yamamoto et al., 2002), might be capable of inducing a similar response. Key downstream responses of TLR3 and TLR4 signaling include the type I interferons, and these might also play a role here, in which case other innate receptors that can induce type I interferons, such as the single-stranded RNA sensor RIG-I (Yoneyama et al., 2004), or DNA sensors, such as IFI16 (Unterholzner et al., 2010), might also have a function similar to TLR3. These other receptors are therefore worth exploring, and, because they are all proinflammatory, inspired the authors to coin the term “transflammation” to describe the potential of these epigenetic modifiers to induce pluripotency.

“Transflammation”: When Innate Immunity Meets Induced Pluripotency: Cell