Over-expression of mir-223 induces m2 macrophage through glycolysis alteration and attenuates lipopolysaccharide-induced sepsis mouse model, a proposal sepsis cell-based therapy

Abstract

Sepsis, a systemic infection with excessive inflammatory symptoms due to dysregulation of immune responses, remains the most concerned health-care problem worldwide with the mortality rate critically beyond the number of death cases in HIV, cancers or stroke. While it is well documented that pathogenesis of sepsis is intimately involved in dysregulation of macrophages, great effort has been made to discover efficacious therapy to control macrophage responses. However, macrophages are the most versatile immune cells with large spectrum of heterogeneous phenotypes and functions. Recently, collection of insights unravel the crucial role of metabolism as an orchestrator of immune regulation, intervention on macrophage metabolic pathway, therefore, is an interesting therapy to attenuate hyper-inflammation in infection. This work aims to investigate the efficacy and mechanism of recent immunomodulation strategies via targeting on metabolic pathway of macrophages. Herein, we report that the overexpression of miR-223 can induce M2 anti-inflammatory macrophage through downregulated glycolytic activities. This benefit paves the way for us to further test cell therapy in sepsis as the adoptive transfer of miR-223 transfected macrophages could ameliorate outcomes of LPS-injected mice. Beside glycolysis, mitochondria also play a crucial role as a central hub connecting metabolic activities and immune responses as demonstrating by reduction of immune response in macrophages after exposed to some mitochondrial uncoupling agents blunting mitochondrial membrane potential. Overall, our work demonstrated the anti-inflammatory effect of metabolic therapy for controlling excessive responses of innate immunity during infection both in vitro and in vivo, suggesting that cellular metabolism could be a promising target to develop effective strategy for better therapeutic treatment in sepsis.