It is well known that females are better protected than their male counterparts against pathogenic infections. However, this advantage comes at a price, and females are also more likely to develop auto-inflammatory disorders, the extreme example being systemic lupus erythematosus (SLE), which is 10 times more frequent in females. While there is direct evidence of a role for the additional female X chromosome in these gender-specific responses (as seen with XXY males, who have the same frequency of SLE occurrence as females), a detailed understanding of how the additional female X chromosome controls immunity remains elusive. In a recent essay, Pinheiro et al. introduced the concept that in addition to X-chromosome-encoded immune genes, microRNAs (miRNAs) could also be at play in the control of sex-based differences in immunity . This hypothesis, which relies on the observation that 10% of all miRNAs are present on the X chromosome, implies that some miRNAs present on the X chromosome exacerbate immune responses.
Relying on the inducible depletion of all miRNAs in mouse macrophages, we have recently made the observation that the overall effect of miRNAs is to positively control inflammation in response to various pathogen-associated molecules . Although counterintuitive, given the repressive action of miRNAs on protein translation, we hypothesised that a subset of miRNAs potentiates inflammatory responses through the control of repressors of NF-κB signalling, one of the critical promoters of inflammation. We identified a set of known repressors of NF-κB signalling that were predicted to be co-regulated by miRNAs from the miR-17∼92 cluster, which comprises miR-19b and miR-18a, among others. Our experiments demonstrated that miR-19 has the strongest effect on the modulation of NF-κB signalling, through its coordinate control of several genes, including A20/Tnfaip3 . In addition, increased intracellular levels of miR-19 exacerbate the production of pro-inflammatory interleukins 8 and 6 by primary fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA), indicating an important role for miR-19 in RA. Such a link between the miR-17∼92 cluster of miRNAs and RA was recently independently confirmed by Trenkmann et al., who demonstrated that the miR-17∼92 cluster of miRNAs is induced by the pro-inflammatory cytokine TNF-α in RA FLS . These authors confirmed our observation that miR-18, similarly to miR-19, controls the expression of A20/Tnfaip3 , and demonstrated that miR-18 contributes to a positive feedback loop, exacerbating NF-κB-driven inflammation in RA FLS . Of note, RA is two to three times more prevalent in females than males.
miR-18 and miR-19 are encoded on chromosome 13 within the miR-17∼92 cluster. In addition, they both have paralogs encoded within the miR-106a∼363 cluster of miRNAs on chromosome X. While the role of the additional copies of miR-19 and miR-18 on chromosome X remains poorly defined, it is nonetheless apparent from mice lacking miR-106a∼363 that these copies are not essential to development . However, these copies directly contribute to the overall miR-18 and miR-19 intracellular concentration, as evidenced experimentally: X-chromosome-encoded miR-19b represents at least 5% of all miR-19b molecules present in cancerous B cells . Further studies are clearly required to assess the contribution of X-chromosome-encoded miR-19 and miR-18 to the function of these miRNAs in the modulation of inflammation. Nevertheless, our findings and those of Trenkmann et al. suggest that the hypothesis of Pinheiro et al. does have credible support, and that these two miRNAs potentially play a role in sex-based differences in immunity.