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The Enigma of Circular RESEARCH HIGHLIGHTS this model. Tape stripping increased stimulates ILC2s to produce IL-4 the number of tuft cells in the small and IL-13 that stimulate IL-25 intestine and their expression of production by tuft cells, which Il25 mRNA. Mice lacking tuft cell- further promotes ILC2 activation. Getty Credit: specific expression of IL-25 did not IL-4 and IL-13 also signal directly to have increased numbers of intestinal mast cells, such that in tape-stripped mast cells after tape stripping. mice with ILC2-specific deficiency Group 2 innate lymphoid cells of IL-4 and IL-13 or with mast cell- (ILC2s) are known targets for IL-33 specific deficiency of IL-4 receptor and IL-25, and experiments with and IL-13 receptor, there is a mice lacking ILC2s showed that decreased oral anaphylaxis response. they are required for the mast cell The authors suggest that this response to tape stripping. Tape pathway connecting mechanical stripping increased the number skin injury to intestinal responses of ILC2s in the small intestine evolved to protect the gut from and increased their expression helminth infections that breach INNATE IMMUNITY of Il4, Il5 and Il13 mRNAs. This the skin barrier. Its relevance to response was abolished in mice atopic responses in humans was The enigma of circular RNA lacking keratinocyte-specific IL-33 shown by the expanded mast cell expression or tuft cell-specific IL-25 populations observed in duodenal Circular RNAs (circRNAs), which are generated through expression, as well as in mice lacking biopsies from patients with atopic back-splicing of pre-mRNAs, are stable and widely expressed, ILC2 expression of the receptors dermatitis compared with controls, but their biological role has remained a mystery. Writing in for IL-33 or for IL-25. Thus, independent of the presence of food Cell, Liu et al. now show that circRNAs bind to and thereby IL-33 and IL-25 have direct, non- allergy or of the serum concentration ‘shield’ protein kinase R (PKR), a pattern recognition receptor redundant effects on ILC2s. of IgE. with antiviral function that is normally activated by double-stranded RNA (dsRNA). Previous work has shown that Kirsty Minton tuft cells and ILC2s are involved Previous studies had implicated circRNAs in innate immune in a feedforward loop during ORIGINAL ARTICLE Leyva-Castillo, J.-M. et al. regulation. For example, it was found that the biogenesis of Mechanical skin injury promotes food anaphylaxis nascent circRNAs is reduced upon viral infection and that intestinal helminth infection. by driving intestinal mast cell expansion. Immunity Similarly, here, the authors showed https://doi.org/10.1016/j.immuni.2019.03.023 enforced expression of circRNAs via plasmids can facilitate (2019) that keratinocyte- derived IL-33 viral infection of human cells. Moreover, patients with a genetic defect leading to the accumulation of intron-lariat-derived RNA circles are more susceptible to viral infections. a Gram-negative mucus-dwelling explaining why disease occurs shortly The authors now demonstrate that stimulation of HeLa cells component of the murine intestinal after weaning. with poly(I:C) or infection with the RNA virus encephalomyo- microbiota. Further experiments Finally, to definitively show carditis virus induces RNaseL activation, which leads to showed that Mucispirillum was Mucispirillum induces colitis in circRNA degradation and the release of PKR inhibition. detectable in Nod2–/– and Cybb–/– Nod2–/–Cybb–/– mice, Jax-fostered The key role of RNaseL in degrading circRNA was confirmed Tac-fostered mice but only showed groups of mice lacking the bacterium in RNaseL-knockout and RNaseL-knockdown cells and by marked accumulation in the Nod2–/– were pretreated with vancomycin and using a synthetic RNaseL activator. Cybb–/– Tac-fostered mice. Notably, orally gavaged with Mucispirillum. PKR is known to undergo auto-phosphorylation in response although Mucispirillum was increased Wild-type, Nod2–/–, Cybb–/– and Nod2–/– to activation by long dsRNAs (>33 bp), but this activation is in the Tac-fostered Nod2–/–Cybb–/– mice Cybb–/– mice showed comparable levels blocked by short dsRNAs (16–33 bp). The authors show that before the onset of colitis, after the of colonization by Mucispirillum — circRNAs, but not their linear cognate RNAs, inhibit development of colitis higher levels of however, only the Nod2–/–Cybb–/– mice dsRNA-induced phosphorylation of PKR. Structural analysis of Mucispirillum were detected in inflamed developed colitis-like disease. the circRNAs revealed that PKR suppression was independent intestinal regions. Mucispirillum is unlikely to of their sequence but required the presence of dsRNA regions, The authors found that pre-colitic contribute to Crohn’s disease in which were typically 16–26 bp in length. –/– –/– Tac-fostered Nod2 Cybb mice have humans, but related bacteria — such Interestingly, the authors also found that peripheral fewer neutrophils in the intestinal as Proteobacteria — have been blood mononuclear cells derived from patients with systemic lumen and lamina propria than control found to be increased in patients lupus erythematosus (SLE) contained less circRNAs, had Tac-fostered wild-type mice, but their with Crohn’s disease. The protective spontaneous RNaseL activation and showed enhanced PKR neutrophils contained higher levels role for antibodies described in this phosphorylation compared with controls. Overexpression of of Mucispirillum. Further experiments study suggests that the identification circRNAs, but not their linear counterparts, attenuated suggested that impaired recruitment of potentially colitogenic bacterial and killing activity of neutrophils in species in humans could enable the aberrant PKR activation in these cells. the Nod2–/–Cybb–/– mice leads to the development of therapeutic vaccines These studies demonstrate that circRNAs can modulate accumulation of Mucispirillum and onset for patients with Crohn’s disease. innate immunity to viruses and reveal an unexpected of colitis in these animals. The authors Yvonne Bordon connection between circRNAs and the autoimmune disease SLE. Alexandra Flemming also found that maternal IgG and IgA ORIGINAL ARTICLE Caruso, R. et al. A specific antibodies specific for Mucispirillum gene-microbe interaction drives the ORIGINAL ARTICLE Liu, C.-X. et al. Structure and degradation of circular RNAs development of Crohn’s disease-like colitis in protect against colitis development regulate PKR activation in innate immunity. Cell https://doi.org/10.1016/j.cell.2019. mice. Sci. Immunol. 4, eaaw4341 (2019) in Tac-fostered Nod2–/–Cybb–/– mice, 03.046 (2019) NATURE REVIEWS | IMMUNOLOGY VOLUME 19 | JUNE 2019 | 351.
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