Mounting evidence supports that sepsis-associated immunosuppression increases mortality. As potential contributors to poor sepsis outcomes, myeloid-derived suppressor cells, which are Gr1+ CD11b+ innate-immune cell progenitors unable to differentiate and possess suppressive activities, expand dramatically in septic mice by a process requiring increased microRNA-21 and microRNA-181b expression. The inhibition of these microRNAs in vivo in septic mice restores Gr1+ CD11b+ cell differentiation and maturation and improves survival. Here, we show that during sepsis-induced generation of myeloid-derived suppressor cells, transcription factor nuclear factor 1 A type represses cyclin-dependent kinase inhibitor p21 to arrest differentiation of Gr1+ CD11b+ cells. Our findings include the following: 1) Gr1+ CD11b+ myeloid cells from late septic mice genetically lacking nuclear factor 1 A type cannot suppress CD4+ T cell proliferation and activation; 2) the reconstitution of nuclear factor 1 A type in microRNA-21 and microRNA-181b-depleted Gr1+ CD11b+ myeloidderived suppressor cells inhibits cyclin-dependent kinase inhibitor p21 and restores the immunesuppressor phenotype; 3) ex vivo nuclear factor 1 A type knockdown in Gr1+ CD11b+ myeloid-derived suppressor cells from late septic mice restores cyclindependent kinase inhibitor p21 expression and promotes monocyte and dendritic cell differentiation; and 4) ectopic nuclear factor 1 A type expression in normal Gr1+ CD11b+ cells generates an immunosuppressive phenotype. We suggest that therapeutically targeting nuclear factor 1 A type during late sepsis might improve survival.
| Identifer | oai:union.ndltd.org:ETSU/oai:dc.etsu.edu:etsu-works-16550 |
| Date | 01 January 2016 |
| Creators | McClure, Clara, Ali, Ekram, Youssef, Dima, Yao, Zhi Q., McCall, Charles E., El Gazzar, Mohamed |
| Publisher | Digital Commons @ East Tennessee State University |
| Source Sets | East Tennessee State University |
| Detected Language | English |
| Type | text |
| Source | ETSU Faculty Works |
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