Editors' ChoiceImmunology

New connections: Putting the brakes on inflammation

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Sci. Signal.  10 Jul 2018:
Vol. 11, Issue 538, eaau2217
DOI: 10.1126/scisignal.aau2217

By targeting multiple pathways, microRNAs limit inflammation during sepsis.

Although the systemic response to bacterial infection can cause rampant production of proinflammatory cytokines, inflammation can also profoundly suppress responses to dangerous secondary infections during sepsis. This suppression is similar to innate immune memory, in which previous exposure to microbial products alters the response of innate immune cells to a subsequent challenge. Screening for microRNAs (miRNAs) that limited macrophage responses to prolonged exposure to endotoxin in vitro, Seeley et al. showed that miR221 and miR222 suppressed inflammatory gene expression. These miRNAs targeted the mRNA encoding Brahma-related gene 1 (Brg1), and the loss of this component of the SWI/SNF nucleosome-remodeling complex silenced the transcription of STAT-dependent genes encoding inflammatory cytokines. Expression of these miRNAs was increased in septic patients when compared with healthy donors, and mice deficient in these miRNAs were protected from inflammatory septic shock. In the Science Signaling Archives, Sisti et al. showed another example of how miRNAs limit inflammation in sepsis. Noting that PTEN expression is increased in septic patients and mice with sepsis, these authors found that the absence of the phosphatase and tensin homolog (PTEN) in myeloid cells increased cytokine production and bacterial burden in mice. Rapamycin-sensitive PTEN activity increased the abundances of miR125b and miR203b, which targeted transcripts encoding the Toll-like receptor adaptor protein MyD88 for destruction. PTEN also physically associated with the Drosha-Dgcr8 miRNA-processing complex and facilitated its nuclear localization. Together, these studies highlight how discrete miRNAs use distinct mechanisms to limit inflammatory responses during sepsis.

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