Overexpressing TREX1 in Macrophages Reduces Injury Following Heart Attack
Researchers here describe an indirect method of inducing greater resistance to damage and regeneration following a heart attack via modulation of macrophage behavior. Macrophages are innate immune cells resident in tissues that play an important role in regeneration and response to injury. The approach taken here is to grant macrophages better control over internally mislocalized DNA, escaped from either the nucleus or mitochondria into the cytosol. This provokes mechanisms intended to react to the presence of infectious pathogens, and is a cause of inflammatory signaling in aged and stressed cells. The better protected macrophages engage in a pattern of behavior that aids tissue regeneration and resilience following the injury of a heart attack.
Noncoding RNAs (ncRNAs) are increasingly recognized as promising therapeutic candidates. Here, we report the development of therapeutic Y RNA 1 (TY1), a synthetic ncRNA bioinspired by a naturally occurring human small Y RNA with immunomodulatory properties. TY1 up-regulates three-prime DNA exonuclease 1 (TREX1), an exonuclease that rapidly degrades cytosolic DNA.
In preclinical models of myocardial infarction (MI) induced by ischemia-reperfusion, TY1 reduced scar size. The cardioprotective effect of TY1 was abrogated by prior depletion of macrophages and mimicked by adoptive transfer of macrophages exposed to either TY1 or Trex1 overexpression. Inhibition of Trex1 in macrophages blocked TY1 cardioprotection. Consistent with a central role for Trex1, TY1 attenuated DNA damage in the post-MI heart.
The key beneficial effects appear to be mediated by extracellular vesicles secreted by TY1-conditioned macrophages. This previously undescribed mechanism - pharmacological upregulation of Trex1 in macrophages - establishes TY1 as the prototype for a new class of ncRNA drugs with disease-modifying bioactivity.