Memory and silence: The role of miRNA machinery in tolerisation of macrophages (360G-Wellcome-109388_Z_15_A)

Macrophages are key mediators of immune responses. Upon encountering microbial antigens, macrophages become activated, which results in pathogen phagocytosis and clearance, and initiation of the adaptive immune response through antigen presentation and inflammatory cytokine secretion. However, uncontrolled macrophage activation can lead to acute systemic inflammation and organ damage (septic shock). Interestingly, exposure to low levels of antigen results in macrophages becoming hypo-responsive following subsequent stimulation (macrophage tolerisation). Furthermore, myeloid cells within a tissue display remarkable heterogeneity in cytokine production. However, the role of population heterogeneity on macrophage tolerisation remains unknown. MicroRNAs are small regulatory RNAs that repress gene expression. They can also decrease noise (stochastic fluctuations) in protein expression and regulate cell-to-cell variability of gene expression. We propose that microRNA-mediated regulation of population heterogeneity is a key mechanism involved in macrophage tolerisation. Here, we will characterize population heterogeneity in wild type and microRNA-deficient (globally or single microRNA) macrophages. We will generate stochastic models to predict phenotypic (tolerisation) switches and validate mathematical outcomes empirically. This research will demonstrate how microRNAs regulate innate immune responses and provide new routes to improve infection and vaccination outcomes.