title: NFI-A disrupts myeloid cell differentiation and maturation in septic mice.
abstract: 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.
authors.affiliation: *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.
authors.forename: Clara
authors.initials: C
authors.lastname: McClure
authors.affiliation: *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.
authors.forename: Ekram
authors.initials: E
authors.lastname: Ali
authors.affiliation: *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.
authors.forename: Dima
authors.initials: D
authors.lastname: Youssef
authors.affiliation: *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.
authors.forename: Zhi Q
authors.initials: ZQ
authors.lastname: Yao
authors.affiliation: *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.
authors.forename: Charles E
authors.initials: CE
authors.lastname: McCall
authors.affiliation: *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 elgazzar@etsu.edu.
authors.forename: Mohamed
authors.initials: M
authors.lastname: El Gazzar
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics* / Q000276:immunology; D004195:Disease Models, Animal; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D056747:Immunomodulation; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics; D022423:Myeloid Cells / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*; D051839:NFI Transcription Factors / Q000235:genetics*; D018805:Sepsis / Q000235:genetics* / Q000276:immunology
chemical_list: D000954:Antigens, Surface; C552691:MIRN18 microRNA, mouse; C531950:MIRN21 microRNA, mouse; D035683:MicroRNAs; D051839:NFI Transcription Factors; C497646:Nfia protein, mouse
keywords: MDSC; immune suppression; inflammation; microRNA; sepsis