C-miR146a corrects the aberrant myeloproliferation and inflammatory responses in miR-146a–deficient mice. (A-B) Reduced proliferation of miR-146a^−/− BMDMs treated with C-miR146a. Bone marrow cells from WT and miR-146a^−/− mice were cultured in the presence of 50 ng/mL of M-CSF for 7 days and treated by using 1 µM of C-miR146a or C-scrRNA. The cell proliferation was measured by using colorimetric XTT assay (A), and the CSF1R expression on CD11b⁺F4/80⁺ cells was quantified by using flow cytometry (B). (C-E) Systemic C-miR146a injections reduced aberrant myeloproliferation of miR-146a^−/− mice in vivo. Ten-month-old WT or miR-146a^−/− female mice (n = 4/group) were injected intravenously by using 10 mg/kg of C-miR146a or PBS daily for 2 weeks and euthanized 1 day after the last injection. Percentages of splenic CD11b⁺Gr1⁺ (C), Ki67⁺CD11b⁺Gr1⁺ (D), and the CSF1R expression on macrophages (E) were analyzed by using flow cytometry. (F) Systemic injections of C-miR146a alleviate exaggerated response to endotoxin in miR-146a^−/− mice. WT or miR-146a^−/− mice were injected intravenously with 5 mg/kg of C-miR146a or C-scrRNA daily for 3 days before LPS challenge (1 mg/kg, intraperitoneally). Blood was collected at the indicated times to analyze IL-6 and TNF-α levels using ELISA. (G-J) C-miR146a treatment restored tolerance to L monocytogenes infection in mice with myeloid cell–specific miR-146a deletion. WT or miR-146a^fl/fl mice injected daily intravenously by using 5 mg/kg of C-miR146a or C-scrRNA were infected with L monocytogenes on day 3 and euthanized on day 6. The liver bacterial load (G), the percentage of weight loss (H), plasma levels of IL-6 (I), and percentages of various hematopoietic cell populations in circulation (J) were assessed. Representative results from at least 2 independent experiments are shown; means ± SEM (n = 5/group). ***P < .001; **P < .01; and *P < .05 compared to untreated or as indicated. CFU, colony-forming unit.