Cytokine responses to LPS in reprogrammed monocytes are associated with the transcription factor PU.1

[摘要] Myeloid-derived suppressor cells (MDSCs) are functionally immunosuppressive cellsthat arise and expand during extensive inflammatory conditions by increasedhematopoietic output or reprogramming of immune cells. In sepsis, an increase of circulating MDSCs is associated with adverse outcomes, but unique traits that can beused to identify increased activity of MDSCs are lacking. By using endotoxin tolerance as a model of sepsis-induced monocytic MDSCs (M-MDSC-like cells), this studyaims to identify the mediator and transcriptional regulator profile associated with MMDSC activity. After analyzing 180 inflammation-associated proteins, a profile of differentially expressed cytokines was found in M-MDSC-like cells versus normal monocytes stimulated with LPS. These cytokines were associated with 5 candidate transcription factors, where particularly PU.1 showed differential expression on both transcriptional and protein levels in M-MDSC-like cells. Furthermore, inhibition of PU.1led to increased production of CXCL5 and CCL8 in M-MDSC-like cells indicating itsrole in regulating the ability of M-MDSC-like cells to recruit other immune cells. Takentogether, the study identifies a unique profile in the pattern of immune mediatorsdefining M-MDSC activity upon LPS stimulation, which offers a functional link to theircontribution to immunosuppression.

[学科分类] 生理学

[关键词] endotoxin tolerance;immunosuppression;inflammation;MDSCs;sepsis