Genetic and pharmacologic inhibition of microRNA-33 (miR-33) in macrophages may attenuate the progression of idiopathic pulmonary fibrosis (IPF) through the improvement of mitochondrial homeostasis and the augmentation of autophagy, according to an article published in JCI Insight.
In this study, the researchers analyzed the concentration of miR-33 in bronchoalveolar lavage (BAL) cells and CD45+ cells isolated from the lungs of people with IPF and healthy controls. They discovered higher levels of miR-33 in monocytes/macrophages and CD45+ cells isolated from the BAL and lungs in patients with IPF than in healthy controls.
However, the CD45– cells of patients with IPF expressed lower levels of miR-33 than those of healthy controls, suggesting a potentially important regulatory role for miR-33 in immune cells and perhaps monocyte/macrophage populations in IPF.
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To directly test the role of miR-33 in immune cells, the researchers generated myeloid-specific miR-33–knockout (KO) mice and subjected them to a bleomycin-induced IPF model. The results suggested a protective effect of macrophage-specific miR-33 ablation, as evidenced by a reduction in collagen content and the expression of profibrotic genes in mice.
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Next, the inflammatory response in myeloid-specific miR-33–KO mice was analyzed by measuring BAL cell recovery and cytokine levels after bleomycin injury. The data indicated that the absence of miR-33 in macrophages may improve mitochondrial homeostasis and increase autophagy while decreasing the inflammatory response.
Further testing showed that the pharmacological inhibition of miR-33 in macrophages via the administration of anti-miR-33 peptide nucleic acids was able to attenuate fibrosis in different in vivo and ex vivo mice and human models of IPF.
“Individual miRNAs can modulate the expression of multiple mRNA targets and can have broad effects on multiple cellular pathways. For this reason, therapies targeting individual miRNAs can have a broader impact than traditional single-molecule/single-target approaches,” Ahangari and colleagues noted.
“Furthermore, the reprogramming of immune cells via miR-33 inhibition could have important implications for a wide variety of diseases characterized by exaggerated immune responses, such as rheumatoid arthritis and asthma.”
Metabolic changes in macrophages represent a key feature in the pathogenesis of chronic lung diseases such as IPF. In pulmonary macrophages, miR-33 regulates key biological and metabolic functions, including bioenergetics, autophagy, mitophagy, and induction of inflammation in response to injury.
Reference
Ahangari F, Price NL, Malik S, et al. MicroRNA-33 deficiency in macrophages enhances autophagy, improves mitochondrial homeostasis, and protects against lung fibrosis. JCI Insight. 2023;8(4):e158100. doi:10.1172/jci.insight.158100
