miR-210 deletion induces a pro-inflammatory status in murine macrophages and alters their polarization towards the pro-reparatory phenotype
Background: Macrophages play fundamental roles in immune regulation and tissue homeostasis, serving as one of the primary cell types that orchestrate tissue repair after injury. MicroRNA-210 is a hypoxia-inducible, small non-coding RNA involved in regulating metabolic adaptation and inflammatory responses during normal repair processes. However, its role in macrophage polarization is not fully understood. Here, we report the impact of miR-210 deletion on macrophage polarization towards a pro-reparatory phenotype. Methods: Bone marrow-derived macrophages were obtained from miR-210 knockout (KO) and wild-type (WT) mice and polarized toward the pro-reparative M2 phenotype. The transcriptomic profile of these cells, as well as their phagocytic capacity, cell energy phenotype, and cytokine production, were comparatively assessed to determine the impact of miR-210 on the polarization process of macrophages into the M2-like phenotype. Results: As compared to WT counterparts, miR-210-KO M0 macrophages exhibited reduced glycolytic activity and diminished metabolic flexibility. However, miR-210 KO macrophages exhibited increased phagocytosis in both M0 and M2 states, potentially as an adaptive response to their metabolic limitations. Transcriptomic analysis revealed distinct clustering between the M0 and M2 states, along with several notable differences in the transcriptional patterns between the two genotypes. Analysis of genes with altered expression levels indicated a higher pro-inflammatory state in resting miR-210 KO macrophages compared to WT control cells. These data were further confirmed by higher levels of IL-6 and TNF-a secreted by miR-210 KO M0 macrophages compared to WT cells. Analysis of the biological processes activated during the polarization process towards M2 phenotypes revealed an incomplete polarization of miR-210 KO cells, which was partly a result of a milder activation of essential mitotic regulators, leading to slower cell cycle progression and reduced proliferation. Conclusion: Our data offer new insights into the role of miR-210 in macrophages and their polarization toward the pro-reparatory phenotype. The fine-tuning involvement of miR-210 in immune responses may have potential implications for chronic inflammation, immune dysfunction, and tissue repair. Overall design: Bone marrow-derived macrophages were obtained from miR-210 knockout (KO) and wild-type (WT) mice and polarized toward the pro-reparative M2 phenotype. The transcriptomic profile of these cells, as well as their phagocytic capacity, cell energy phenotype, and cytokine production, were comparatively assessed to determine the impact of miR-210 on the polarization process of macrophages into the M2-like phenotype.