Inflammatory bowel diseases (Crohn’s Disease and Ulcerative Colitis) are characterised by aberrant myeloid immune activation in the intestine, that damages bowel tissues in genetically susceptible individuals. Globally, approximately 7 million people are currently living with this disease, yet there are few efficacious treatment modalities and no cure. Patients who fail to respond to front-line immunotherapies present with enhanced neutrophil and monocyte inflammatory gene signatures. As such, a dilemma exists in that we cannot block this myeloid arm of the immune response due to the critical need for anti-infection responses and tissue healing. Yet, there are no clear pathways to understand how IBD therapeutics may limit the excessive, tissue destructive inflammation and drive healing processes. To address this challenge, this thesis will focus on understanding myeloid intrinsic control points, namely microRNAs, that have potential to uncover new disease mechanisms and potential therapeutic opportunities. MicroRNAs (miRNAs) are emerging as important regulators of immunity and are differentially expressed in IBD; however, their mechanistic roles in disease progression remain poorly understood. MiR-223 is a myeloid-restricted miRNA, and previous research has identified a critical role for miR-223 in models of infection, colitis and colitis-associated colon cancer. In effect, we propose that miR-223 can act like a rheostat, shaping the mRNA translator of important inflammation signalling, however we understand little of how this may shape the immune landscape of the inflamed intestine and impact mucosal healing. Functionally, miR-223 expression was reduced during macrophage differentiation and following activation with inflammatory cytokines or bacterial LPS, coinciding with decreased expression of RISC components and the myeloid transcription factors, C/EBPβ and PU.1. In contrast, supplementation with miR-223-3p and miR-223-5p mimetics suppressed macrophage inflammatory responses to LPS, reducing expression of pro-inflammatory cytokines and chemokines while promoting a pro-resolving macrophage phenotype. Using in situ hybridization, the dynamic expression of miR-223 across experimental colitis and recovery was identified. MiR-223-/y mice exhibited delayed mucosal healing, increased myeloid infiltration, and disruption of the epithelial stem cell niche. We further mapped the myeloid and macrophage immune compartment along the continuum of inflammation and healing following active colitis, and identified an epithelial stem cell growth differential in MiR-223- /y mice. To begin to identify the mechanistic links that miR-223 can regulate, we showed that STAT3, a key regulator of intestinal regeneration, was hyperactivated in miR-223-/y mice following experimentalcolitis. In vitro studies using miR-223KD macrophages demonstrated regulation of the IL-6 cytokine family and downstream STAT3 signalling. Co-culture experiments with colonic epithelial organoids further revealed that macrophage-derived miR-223 influences epithelial regeneration via STAT3-dependent pathways. Collectively, this work identifies miR-223 as a critical myeloid-derived regulator of intestinal inflammation, epithelial repair, and stem cell niche maintenance.