Micro-balancing innate immunity to Salmonella

Abstract

EMBO J 30 10, 1977–1989 (2011); published online April 05 2011

MicroRNAs are 19–24 nt-long RNAs that post-transcriptionally regulate eukaryotic gene expression. Beside their important roles in patterning and development, miRNAs also orchestrate responses to pathogen infections. In this issue of The EMBO Journal, Schulte et al (2011) investigate the miRNA response of mammalian cells to the intracellular bacterium Salmonella. They find that Salmonella triggers highly specific and robust alterations to the expression of a subset of host miRNAs. In macrophages, these alterations notably include the rapid downregulation of let-7 MIRNA gene family members, following extracellular sensing of bacterial lipopolysaccharides (LPS) via Toll-like receptor 4 (TLR4). The authors identify two interleukins (IL-6 and IL-10) as novel targets of Let-7 and suggest that Salmonella infection rapidly relieves IL-6 and IL-10 from negative control by let-7, thereby potentiating the immune response. Intriguingly, while IL-6 is pro-inflammatory, IL-10 prevents the detrimental consequences of systemic inflammation, suggesting that the observed response is tightly balanced and, hence, biologically relevant.

Figure 1

Plant and mammalian strategies for miRNA-directed, PAMP-triggered immunity. (A) In Arabidopsis, sensing of bacterial flagellin by the cognate receptor FLS2 induces transcription of miR-393a. This miRNA represses a key component of the auxin signalling pathway, which negatively regulates plant defence. Resistance is thus achieved, in this case, by inducing a repressor of a negative regulator of innate immunity. (B) In mouse macrophages, bacterial-derived LPS is sensed by TLR4 to promote rapid downregulation of let-7 MIRNA family members through as yet unidentified mechanisms (?). Downregulation of let-7 promotes enhanced accumulation of its targets, IL-6 and IL-10, with the former displaying pro-inflammatory properties and the latter preventing systemic inflammation. This results in the mounting of a balanced innate immune response that proceeds, therefore, through concomitant repression of a repressor of a positive regulator of defence, and repression of a repressor of a negative regulator of defence.