S100A9 maintains myeloid-derived suppressor cells in chronic sepsis by inducing miR-21 and miR-181b
Authors: Mohamed El Gazzar
Ajinkya Kumbhare
Charles E McCall
Dima Youssef
Isatou Bah
Tuqa Alkhateeb
Zhi Q Yao
Journal: Molecular Immunology (2019)
Discipline: IMMUNOLOGY
Keywords: Immune suppression; MDSC; S100A9; Sepsis.
Affiliations: Department of Internal Medicine, East Tennessee State University College of Medicine, Johnson City, TN, United States., Department of Internal Medicine, Section of Molecular Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, United States., Department of Internal Medicine, East Tennessee State University College of Medicine, Johnson City, TN, United States. Electronic address: .

Abstract:  Myeloid-derived suppressor cells (MDSC) expand during sepsis, suppress both innate and adaptive immunity, and promote chronic immunosuppression, which characterizes the late/chronic phase of sepsis. We previously reported that the transcription factors Stat3 and C/EBPŒ≤ synergize to induces the expression of microRNA (miR)-21 and miR-181b to promote MDSC expansion in a mouse model of polymicrobial sepsis that progresses from an early/acute proinflammatory phase to a late/chronic immunosuppressive stage. We also showed that Gr1+CD11b+ cells, the precursors of MDSCs, from mice genetically deficient in the inflammatory protein S100A9 lack miR-21 or miR-181b in late sepsis, and are not immunosuppressive. In the present study, we show that S100A9 induces miR-21 and miR-181b during the late sepsis phase. We find that S100A9 associates with and stabilizes the Stat3-C/EBPŒ≤ protein complex that activates the miRNA promoters. Reconstituting Gr1+CD11b+ cells from S100A9 knockout mice with late sepsis with S100A9 protein restores the Stat3-C/EBPŒ≤ protein complex and miRNA expressions, and switches the Gr1+CD11b+ cells into the immunosuppressive, MDSC phenotype. Importantly, we find that this process requires IL-10 mediated signaling, which induces S100A9 translocation from the cytosol to the nucleus. These results demonstrate that S100A9 promotes MDSC expansion and immunosuppression in late/chronic sepsis by inducing the expression of miR-21 and miR-181b. 

Retracted: No

PubPeer comments:
 Methods on Bacterial concentration and protein concentration determination were not included in the methodology. Also, another question is on the provided (1) bacterial concentration (3.8 u00d7 10^10 cells well) and (2) protein concentration (320 u03bcg u03bcl) which represent six (6) different strains (Cell-free tellurite reduction assay). The source of the protein concentration in solubilized cells (SC) are six different strains as follows (in Figure 8 of the paper); 1. wild-type E. coli (WT) 2. wild-type harboring the empty pHSG398 plasmid vector (WT P1) 3. recombinant E. coli A1 (A1) 4. wild-type harboring the empty pTrc99A plasmid vector (WT-P2) 5. ORF1- expression clone (A1-ORF1) 6. ORF2-expression clone (A1-ORF2) The values of the bacterial concentration and protein concentration does not affect the over-all result or observation in the experiment since the main objective of cell-free tellurite reduction assay is only to observe whether live-intact cells are required for tellurite reduction to ensue.  , 
 Methods of bacterial and protein concentration determination were not indicated in the methodology. ,