**Background:** The lung is constantly exposed to environmental pathogens and toxins, making it susceptible to inflammatory conditions such as acute lung injury (ALI), asthma, chronic obstructive pulmonary disease (COPD), and COVID-19. MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression post-transcriptionally. miR-223 is a conserved miRNA highly expressed in myeloid lineage cells, particularly granulocytes and their precursors. It plays a critical role in regulating inflammation by targeting multiple genes involved in immune cell differentiation, polarization, and cytokine production. This review provides a comprehensive overview of miR-223's involvement in pulmonary inflammation, aiming to enhance understanding of its clinical implications.
**Methods:** The authors conducted a narrative review of the literature, summarizing studies on miR-223 biogenesis, expression regulation, and function in various cell types (granulocytes, macrophages, endothelial cells, epithelial cells, and dendritic cells). They also reviewed studies on miR-223's role in pulmonary inflammatory diseases, including ALI, asthma, COPD, COVID-19, tuberculosis, sarcoidosis, and pulmonary fibrosis. The review includes data from in vitro, in vivo, and clinical studies, with a focus on molecular targets and signaling pathways.
**Key Results:** miR-223 is highly conserved and located on the X chromosome (q12). Its expression is regulated by transcription factors such as PU.1, C/EBPs, and PPAR-γ (upregulators) and KLF6 (downregulator). In granulocytes, miR-223 targets Mef2c, NFIA, and C/EBPα to regulate proliferation and differentiation. In macrophages, miR-223 targets Pknox1, Rasa1, NFAT5, TRAF6, STAT3, and NLRP3 to modulate polarization (M1 vs. M2) and proinflammatory cytokine release. In endothelial cells, miR-223 targets ICAM-1 and NLRP3 to attenuate inflammation. In epithelial cells, miR-223 targets NLRP3 and microvesicles to reduce inflammation. In dendritic cells, miR-223 targets NLRP3, C/EBPβ, Irak1, Rhob, Rasa1, Cfla, and Kras to regulate differentiation and function.
In ALI, miR-223 overexpression alleviates LPS-induced injury by targeting NLRP3, RHOB, and TLR4/NF-κB signaling. miR-223 also regulates macrophage polarization toward M2 phenotype via Nfat5 and Rasa1. In asthma and COPD, miR-223 is upregulated in bronchial brushings and sputum, and it targets NF-κB, PARP-1, IKKα, IGF-1R, Mef2c, TGF-β receptor 3, CDK2, and p53 to modulate inflammation, cell proliferation, and apoptosis. In COVID-19, miR-223-3p directly targets the SARS-CoV-2 S protein to inhibit viral replication and reduces cytokine storm by downregulating IL-8, IL-18, IL-1β, and MCP-1. In tuberculosis, miR-223 targets CXCL2, CCL3, and IL-6 to reduce neutrophil recruitment. In sarcoidosis, miR-223 is downregulated in BAL fluid and targets NLRP3 and NF-κB. In pulmonary fibrosis, miR-223 expression decreases with increasing fibrosis.
**Clinical Implications:** miR-223 shows promise as a diagnostic and prognostic biomarker for pulmonary inflammatory diseases. Its expression levels are altered in various conditions, including ALI, asthma, COPD, COVID-19, tuberculosis, and sarcoidosis. Therapeutic strategies using miR-223 mimics or inhibitors have been tested in animal models, showing potential to reduce inflammation and tissue damage. For example, miR-223 mimics protect against atherosclerosis, radiation-induced heart disease, and dry eye disease by targeting NLRP3 and other pathways. miR-223 inhibitors have been used to upregulate NLRP3 in gout arthritis. The review highlights the urgent need for clinical trials to evaluate miR-223-targeted therapies in pulmonary inflammation, particularly given the lack of specific treatments for ALI/ARDS and the ongoing COVID-19 pandemic.