Balancing inflammatory signaling in hematopoiesis: roles of MIRC11 and miR-146a

Inflammatory signaling regulates hematopoietic stem and progenitor cell (HSPC) function, but mechanisms that maintain inflammatory signaling within a physiological range remain incompletely understood. MicroRNAs (miRNAs) are important regulators of immune signaling pathways. In this report we hypothesized that MIRC11 miRNAs (miR-23a, miR-24-2, and miR-27a) and miR-146a which oppositely regulate NF-κB activity, function to fine-tune inflammatory responses in hematopoietic cells.

Inflammatory gene expression in mmu-Mirc11^-/- HSPCs was analyzed by RNA sequencing. To examine functional interactions between mmu-MIRC11 and mmu-miR-146a miRNAs in vivo, we generated Mirc11^-/-Mir146a^-/- double knockout mice. Hematopoietic populations were characterized by flow cytometry, and inflammatory responses were assessed in bone marrow-derived macrophages following Toll-like receptor (TLR) stimulation.

RNA sequencing revealed reduced activation of inflammatory pathways including interferon, TNF, IL-6, and TLR signaling in mmu-MIRC11-deficient HSPCs. Double knockout mice were viable and exhibited modest changes in the lineage skewing observed in Mirc11^-/- mice but did not rescue the progressive bone marrow failure associated with mmu-miR-146a deficiency. In macrophages, combined loss of mmu-MIRC11 and mmu-miR-146a produced gene-specific effects on inflammatory responses, frequently enhancing cytokine expression compared with single mutants.

These findings demonstrate that MIRC11 promotes inflammatory signaling in hematopoietic cells and that interactions between MIRC11 and miR-146a regulate inflammatory gene expression in a context-dependent manner. Together, these results highlight the complexity of miRNA-mediated control of immune signaling and suggest that coordinated manipulation of miRNA pathways may enable selective modulation of inflammatory responses.