Author Of 1 Presentation
PS02.05 - Nanomodulation of microRNAs in Macrophages
Multiple Sclerosis (MS) is characterized by central nervous system infiltration of peripheral immune cells, the largest fraction of which are macrophages. The macrophage role in MS is multifaceted, in a pro-inflammatory or ‘M1’ state instructing demyelination and axonal loss, while the anti-inflammatory ‘M2’ state holds a key role in tissue repair and regeneration. Previously, we have identified that IL-10 inhibition of miR-155 is a prominent mechanism utilized by macrophages to maintain an M2 state. Moreover, using a miR-155 floxed x LysMCre model, where miR-155 is specifically deleted from myeloid cells, there was reduced disease onset and less lesion burden in the experimental autoimmune encephalomyelitis (EAE) animal model. Thus, we hypothesize miR-155 inhibition may favorably modulate the macrophage population to an ‘M2’ or pro-repair phenotype, reducing inflammation, alleviating disease progression, mimicking an IL-10 mediated effect.
To investigate the therapeutic potential of a miR-155 anti-miRNA oligonucleotide (AMO) packaged in nanoparticle-based carriers to enhance uptake into macrophages.
4 AMOs were investigated for their ability to inhibit mir-155 in Raw 264.7 and bone marrow-derived macrophages (BMDM). The downstream effect of macrophage pro-inflammatory function in response to mir-155 inhibition was examined by measuring a range of macrophage polarisation parameters, including pro-inflammatory cytokine and nitric oxide (NO) production, expression of M2 markers Arginase-1 and CD206, two markers intricately tied with metabolism in the context of polarisation. PLGA and novel star-shaped polypeptides were also assessed for in vitro macrophage delivery.
A locked nucleic acid (LNA) modified AMO showed the most promising results for mir-155 inhibition in both Raw 264.7 and BMDM. In further studies we show changes in expression of mir-155 target genes that mimic an IL-10 mediated phenotype, while mir-155 independent increases in M2 marker Arginase-1 suggest a more M2 like phenotype. Additionally, star-shaped polypeptides demonstrate the capacity for AMO delivery to BMDM.
mir-155 inhibition can be achieved through delivery of an AMO, and mimics crucial aspects of an IL-10 mediated macrophage phenotype. Star polypeptides represent a promising avenue towards macrophage-specific uptake and future in vivo delivery in MS animal models.