Proinflammatory Role of let-7 miRNAs in Experimental Asthma?

Polikepahad et al. (1) recently reported that let-7 microRNAs have proinflammatory roles because inhibition of let-7a to let-7d alleviated the features of experimental asthma. However, there are serious drawbacks in the study design and interpretations. First, the in vivo findings in an IL-13-driven asthma model are exactly opposite to their in vitro observations where they found that let-7 inhibited IL-13. Although they suggest that this discrepancy could be because of secondary and tertiary effects of let-7 inhibition on the other proinflammatory genes, this is at best speculative and no evidence is provided in support. Second, because there was no change in let-7 in the asthma model, it is unclear why they chose to inhibit only a few selected let-7 members, whereas abundant let-7 members like let-7f were not inhibited. This is worrisome because all let-7 members share the seed region match with IL-13, and a loss of function experiment cannot be properly done unless all members were inhibited. Third, they do not report a more relevant gain-of-function experiment where any of the let-7 members could have been used to inhibit IL-13 in vivo. This is particularly surprising because it would be the logical follow-through of their in vitro data. In absence of this critical experiment, we consider their counterintuitive conclusions to be unreliable and possibly due to existence and/or bystander increase in other let-7 members due to Dicer negative feedback loop (2, 3). Thus the proinflammatory role of Let-7 in asthma is not well justified and further investigations are required to determine the exact role of let-7 in asthma.