TLR7-mediated immune response of renal myeloid-derived suppressor cells via RUNX1-KLF4 in systemic candidiasis.

TLR7 and myeloid-derived suppressor cells (MDSCs) play unique roles in determining host resistance to candidiasis. However, the precise mechanisms of TLR7 in MDSC differentiation and functionality during Candida albicans infection remain elusive. We found that compared with wild-type mice, kidney injuries and inflammation were significant in Tlr7 knockout mice. Tlr7 deficiency impeded the differentiation and maturation of mature myeloid cells and stimulated MDSC expansion. Furthermore, the absence of Tlr7 enhanced the immunosuppressive ability of infected MDSCs. Contrarily, the treatment of the TLR7 agonist R848 directly acted on MDSCs, leading to the differentiation and maturation of MDSCs and blocking their immunosuppressive activity. TLR7+ granulocytic MDSCs (G-MDSCs) significantly exhibited the enhanced expression of RUNX1 and KLF4. Subsequently, prevention of RUNX1 activity with Ro5-3335 or treatment with KLF4-activating agent APTO-253 affected the differentiation and maturation of G-MDSCs in vitro. Taken together, our results identified a function of TLR7 in modulating the MDSC response and suggested that RUNX1 and KLF4 were key transcription factors in regulating TLR7-mediated G-MDSC immune responses.