The mTOR signal regulates myeloid-derived suppressor cells differentiation and immunosuppressive function in acute kidney injury.
The mammalian target of rapamycin (mTOR) signal controls innate and adaptive immune response in multiple immunoregulatory contexts. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of myeloid cells of potent immunosuppressive capacity. In this study, we aimed to investigate the role of MDSCs in the protection of acute kidney injury (AKI) and the regulation of mTOR signal on MDSC's protective role in this context. In mice AKI model, rapamycin administration was associated with improved renal function, restored histological damage and decreased CD4+and CD8+T-cell infiltration in kidney tissue. MDSCs, especially CD11b+Ly6G+Ly6ClowG-MDSCs were recruited to the injured kidney following the interaction of CXCL1, CXCL2 and their receptor CXCR2 after inhibiting mTOR signal with rapamycin treatment. The adoptive transfer of rapamycin-treated MDSCs into the mice with AKI significantly improved the renal function, ameliorated histologic damages and limited the infiltration of T cells in kidney tissue. In addition, the expression of pro-inflammatory cytokines IL-1β and IFN-γ mRNA was downregulated while the expression of TGF-β1 and Foxp3 mRNA was upregulated in kidney tissue after transferring rapamycin-treated MDSCs. Adoptive transfer of rapamycin-treated MDSCs also downregulated the serum levels of IL-1β, IL-6 and IFN-γ and upregulated the serum levels of TGF-β1 compared with the IR group and PBS-treated MDSC group. In in vitro study, inhibiting mTOR signal regulated the induction of MDSC towards the CD11b+Ly6G+Ly6ClowG-MDSC subset. The ability to suppress T-cell proliferation of both bone marrow-derived CD11b+Ly6G+Ly6ClowG-MDSCs and CD11b+Ly6G-Ly6ChighM-MDSCs was enhanced by mTOR signal inhibition via upregulating the expression of Arginase-1 and iNOS. Accordingly, both G-MDSCs and M-MDSCs presented downregulated runx1 gene expression after rapamycin treatment. Taken together, our results demonstrated that MDSCs ameliorated AKI and the protective effect was enhanced by mTOR signal inhibition via promoting MDSCs recruitment, regulating the induction of MDSCs and strengthening their immunosuppressive activity.
Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China.|Shanghai Key Laboratory of Organ Transplantation, Shanghai, China.
Chao
C
Zhang
Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China.|Shanghai Key Laboratory of Organ Transplantation, Shanghai, China.
Shuo
S
Wang
Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China.
Jiawei
J
Li
Shanghai Key Laboratory of Organ Transplantation, Shanghai, China.
Weitao
W
Zhang
Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China.
Long
L
Zheng
Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China.|Shanghai Key Laboratory of Organ Transplantation, Shanghai, China.
Cheng
C
Yang
Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China.|Shanghai Key Laboratory of Organ Transplantation, Shanghai, China.|Shanghai Public Health Clinical Center, Fudan University, Shanghai, China.
Tongyu
T
Zhu
Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China.|Shanghai Key Laboratory of Organ Transplantation, Shanghai, China.|Department of Transfusion, Zhongshan Hospital, Fudan University, Shanghai, China.
Ruiming
R
Rong
D058186:Acute Kidney Injury / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001119:Arginase / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D007166:Immunosuppressive Agents / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells; D000072737:Myeloid-Derived Suppressor Cells / Q000378:metabolism* / Q000473:pathology; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
D007166:Immunosuppressive Agents; D053583:Interleukin-1beta; D015850:Interleukin-6; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D001119:Arginase; D020123:Sirolimus