MicroRNA-223 modulates the IL-4-medicated macrophage M2-type polarization to control the progress of sepsis

MicroRNAs play a variety of roles in the progress of inflammation. Herein, we investigated the roles of miR-223 in governing macrophage polarization balance in the progress of sepsis. We firstly observed that miR-223 was down-regulated at the early phase and up-regulated at the late phase of sepsis in macrophages; the levels of miR223 were positively correlated to the ratio of M2 macrophages during sepsis. In miR-223 knockout mice, we observed that miR-223 was dispensable for efficient pro-inflammatory responses, but was required for efficient M2-associated phenotype and function. miR-223 deletion increased clinical scores of sepsis, leading to increased mortality in septic mice. Furthermore, we found that miR-223 expression in M2-type macrophages was controlled by interleukin (IL)-4, but not IL-10; IL-4 antibodies were able to downregulate the levels of miR-223, increased the expression of targeted genes Nfat5 and Rasa1, reduced the ratio of M2 macrophages, resulting in a decreased survival rate in septic mice. Meanwhile, miR-223 deficient macrophages appeared a markedly decreased M2-type polarization when induced by IL-4, but did not affect macrophages skew to M2 phenotype induced by IL-10. Taken together, our results demonstrate that miR-223 acts as an important regulator to modulate IL-4-meditated M2-type polarization of macrophages via targeting to Nfat5 and Rasa1 to control the progress of sepsis.

Automated summary

miR-223 plays a crucial role in modulating macrophage polarization balance during sepsis, by targeting Nfat5 and Rasa1 to control IL-4-mediated M2-type polarization. miR-223 deletion increases clinical scores and mortality in septic mice, indicating its important regulatory function in sepsis.