Rapamycin attenuates acute lung injury induced by LPS through inhibition of Th17 cell proliferation in mice

Th17 cells have been confirmed to increase neutrophils through cytokine secretions. ALI/ARDS are characterized as neutrophil infiltration in inflammation cases; however, there is conflicting information concerning the role of Th17 cells in ALI/ARDS, as well as their potential treatment value. We measured Th17-linear cytokines in the plasma of patients with sepsis-related ARDS. The consistently high levels of IL-17 and IL-22 in the nonsurvivors suggested that overreaction of the Th17-mediated immune response may be a risk factor for poor outcomes. Th17 linear cytokines were also increased in an LPS-induced murine model of acute lung injury, along with neutrophil accumulation. The mice that completely lacked IL-17 failed to accumulate and activate neutrophils. Lung inflammation was obviously attenuated in the IL-17(-/-) mice. Meanwhile, the neutrophil count was markedly increased in the healthy WT mice challenged with recombinant IL-22 and IL-17. Rapamycin attenuated lung injury by inhibiting the differentiation of Th17 cells through ROR gamma t and STAT3 dysfunction. Furthermore, we demonstrated that SOCS3 and Gfi1, which were responsible for the molecular suppression of ROR gamma t and STAT3, were up-regulated by rapamycin. These results point toward a pivotal view to treatment of ALI through weakening the proliferation of Th17 cells with rapamycin.