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  • mTOR limits the recruitment of CD11b+Gr1+Ly6Chigh myeloid-derived suppressor cells in protecting against murine immunological hepatic injury.

mTOR limits the recruitment of CD11b+Gr1+Ly6Chigh myeloid-derived suppressor cells in protecting against murine immunological hepatic injury.

Journal of leukocyte biology (2014-02-27)
Yan Zhang, Yujing Bi, Hui Yang, Xi Chen, Huanrong Liu, Yun Lu, Zhengguo Zhang, Jiongbo Liao, Shan Yang, Yiwei Chu, Ruifu Yang, Guangwei Liu
ABSTRACT

The mTOR pathway integrates diverse environmental inputs, including immune signals and metabolic cues, to direct the innate and adaptive immune responses. MDSCs are a heterogeneous cell population that plays a crucial regulatory effect in immune-related diseases. However, whether mTOR signaling affects the functions of MDSCs remains largely unknown. Here, we show that mTOR signaling is a pivotal negative determinant of MDSC recruitment in IMH disease. In the context of IMH, inhibition of mTOR with rapamycin in CD11b⁺Gr1⁺ MDSCs mediates protection against IMH and serves as a functional, suppressive immune modulator that results in increased CD11b⁺Gr1⁺Ly6C(high) MDSC recruitment to inflammatory sites. In agreement with this, mTOR down-regulation promotes CD11b⁺Gr1⁺Ly6C(high) MDSC migration in vitro and in vivo. Mechanistically, mTOR activity down-regulation in MDSCs induced iNOS expression and NO production. Pharmacologic inhibition of iNOS completely eliminated MDSC recruitment. This study identifies MDSCs as an essential component for protection against IMH following rapamycin treatment. Rapamycin treatment or mTOR inhibition promotes CD11b⁺Gr1⁺Ly6C(high) MDSC recruitment and is critically required for protection against hepatic injury. This study further validates the targeting of mTOR signaling as a potential therapeutic approach to IMH-related diseases.

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