The inflammatory response results from a carefully balanced pattern of gene expression that is designed to control microbial infection, while limiting damaging inflammation. Excessive production of inflammatory cytokines contributes to the progression of the infection-triggered systemic inflammatory condition, sepsis. In what may be a protective response against this deleterious outcome, macrophages become tolerant to prolonged treatment with pro-inflammatory agents such as lipopolysaccharide (LPS). Tolerant macrophages reduce production of pro-inflammatory cytokines in favor of anti- inflammatory and anti-microbial genes upon re-stimulation. However, the molecular basis of this phenomenon is not clearly defined. Diverse mechanisms can lead to the selective gene expression seen during processes such as the induction of tolerance. MicroRNAs (miRNAs), in particular, have emerged as important post-transcriptional regulators of selective gene expression. Thus far, no miRNA has been found to selectively affect transcription in a way that recapitulates the gene expression changes noted during LPS tolerance. However, we have identified a number of miRNA species that are expressed in macrophages after prolonged exposure to LPS treatment and which appear to selectively modulate the expression of inflammation-related genes. miR-222 was the most highly expressed of the miRNAs identified in our screen, and our preliminary results suggest that miR-222 targets the Brg1 subunit of the SWI/SNF remodeling complex in macrophages. This targeting leads to attenuated production of a subset of inflammatory cytokines; however, it leaves TLR4 signaling intact. Given the kinetics of miR-222 expression, and the fact that the newly defined miR-222 target, Brg1, has been shown to mediate chromatin remodeling at selective promoters during LPS tolerization, we hypothesize that miR-222 may be a bona fide regulator of tolerance. We plan to utilize genomic analysis and a novel genetic model to validate the role of miR-222 as a regulator of tolerance. This project has exciting implications for the design of therapeutics to acutely induce tolerance and combat inflammation during sepsis progression.
Sepsis affects hundreds of thousands each year in the United States alone, with an estimated 20-30% mortality rate in spite of current treatments. In experimental models, pre-treatment with sub-lethal doses of the bacterial component lipopolysaccharide (LPS) induces a state of 'LPS tolerance' that reduces lethality from septic shock. We hypothesize that a particular microRNA (miR-222) regulates LPS tolerance, and believe that our studies will help establish this regulator as a novel and specific target that can be modulated to counter inflammation or mimic aspects of tolerance, thereby presenting a potential new method of treating sepsis.
|Seeley, John J; Baker, Rebecca G; Mohamed, Ghait et al. (2018) Induction of innate immune memory via microRNA targeting of chromatin remodelling factors. Nature 559:114-119|