NFI-A disrupts myeloid cell differentiation and maturation in septic mice.

J Leukoc Biol

*Departments of Internal Medicine and Center for Inflammation, Infectious Diseases and Immunity, East Tennessee State University College of Medicine, Johnson City, Tennessee, USA; and Department of Internal Medicine, Section of Molecular Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA

Published: January 2016

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(+) myeloid-derived suppressor cells inhibits cyclin-dependent kinase inhibitor p21 and restores the immune-suppressor phenotype; 3) ex vivo nuclear factor 1 A type knockdown in Gr1(+) CD11b(+) myeloid-derived suppressor cells from late septic mice restores cyclin-dependent 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.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4673479PMC
http://dx.doi.org/10.1189/jlb.4A0415-171RRDOI Listing

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