Research ArticleImmunology

Nuclear PTEN enhances the maturation of a microRNA regulon to limit MyD88-dependent susceptibility to sepsis

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Sci. Signal.  01 May 2018:
Vol. 11, Issue 528, eaai9085
DOI: 10.1126/scisignal.aai9085

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PTEN and sepsis

The uncontrolled production of proinflammatory factors is a leading cause of organ dysfunction during sepsis. As well as being activated by microbial products, Toll-like receptors (TLRs) are activated by injury-associated danger signals. Almost all TLR-dependent cytokine production depends on the adaptor protein MyD88. Sisti et al. found that the abundance of the mRNA encoding the lipid and protein phosphatase PTEN was increased in mice after surgical induction of sepsis. Inhibition or knockdown of PTEN during sepsis resulted in increased inflammation, tissue injury, and mortality, which was associated with an increase in MyD88 abundance. PTEN activation induced the production of microRNAs that targeted Myd88 mRNA. Preventing the nuclear translocation of PTEN resulted in the cytosolic localization of a microRNA-processing complex and a failure to target MyD88. Together, these results suggest that the PTEN-dependent microRNA generation targets MyD88 to limit the damaging effects of sepsis.

Abstract

Sepsis-induced organ damage is caused by systemic inflammatory response syndrome (SIRS), which results in substantial comorbidities. Therefore, it is of medical importance to identify molecular brakes that can be exploited to dampen inflammation and prevent the development of SIRS. We investigated the role of phosphatase and tensin homolog (PTEN) in suppressing SIRS, increasing microbial clearance, and preventing lung damage. Septic patients and mice with sepsis exhibited increased PTEN expression in leukocytes. Myeloid-specific Pten deletion in an animal model of sepsis increased bacterial loads and cytokine production, which depended on enhanced myeloid differentiation primary response gene 88 (MyD88) abundance and resulted in mortality. PTEN-mediated induction of the microRNAs (miRNAs) miR125b and miR203b reduced the abundance of MyD88. Loss- and gain-of-function assays demonstrated that PTEN induced miRNA production by associating with and facilitating the nuclear localization of Drosha-Dgcr8, part of the miRNA-processing complex. Reconstitution of PTEN-deficient mouse embryonic fibroblasts with a mutant form of PTEN that does not localize to the nucleus resulted in retention of Drosha-Dgcr8 in the cytoplasm and impaired production of mature miRNAs. Thus, we identified a regulatory pathway involving nuclear PTEN–mediated miRNA generation that limits the production of MyD88 and thereby limits sepsis-associated mortality.

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