Title : Nanoparticle delivery of mitochondria-associated microRNA regulating inflammation in the central nervous system
Abstract:
Traumatic brain injury (TBI) is a leading cause of long-term impairments in higher cognitive function. Ongoing destructive secondary injury events occur minutes to days after the initial insult characterized by a cascade of pervasive biochemical and pathophysiological stressors including mitochondrial dysfunction, free radical-mediated oxidative damage, and inflammation. A rapid and sustained phase of mitochondrial dysfunction after TBI impacts a number of important cellular events. Our recent studies revealed that the levels of several mitochondria-associated miRNAs regulating inflammation (e.g., miR-146a) are altered early on after TBI at times that corresponds to a loss of mitochondrial function. Knowledge of the temporal changes in mitochondria associated miRNA levels after TBI provides an opportunity to target specific miRNA at specific time points. Two validated targets of miR-146a (TRAF6 and IRAK1) are thought to be involved in the differential expression of the M1 pro-inflammatory and M2 anti-inflammatory macrophage/microglia phenotypes. Recently, we employed a peptide-based miRNA nanoparticle delivery approach as a strategy to favor M2 microglia/macrophage expression and promote tissue repair following TBI. Specifically, we found that in vitro and in vivo nanoparticle delivery of miR-146a mimic reduced expression of TRAF6 and IRAK1, decreased expression of several pro-inflammatory markers (e.g., Marco, IL-6, and Nos2) and increased expression of anti-inflammatory markers (IL-4, Mrc1, and Arg1). The outcomes of our studies suggest a temporally dynamic interaction of miRNAs with mitochondria and point a potential role for mitochondria in directing the cellular function of specific miRNA regulating inflammatory responses in the central nervous system (CNS). Our studies also demonstrate the use of a peptide-based nanoparticle approach to effectively deliver miRNA mimics as a way to target specific miRNA activities following TBI and possibly other CNS-related injury events.
Audience take away:
• The audience will gain a better understanding of signaling events regulating inflammatory miRNA expression after traumatic brain injury.
• The ability to manipulate the activity of miRNAs regulating inflammation has therapeutic potential in the treatment of traumatic brain injury.
• Regulation of key mitochondria- associated inflammatory miRNA in response to CNS injury may be tissue and cell specific.
• Our current studies utilize microinjections of miR-146a containing nanoparticles directly into the CNS tissue, which is not clinically optimal. Therefore, identification of delivery strategies that obviate the need for direct injections into the CNS is a high priority.
