Myeloid Cell-Specific Knockout of NFI-A Improves Sepsis Survival.
Myeloid progenitor-derived suppressor cells (MDSCs) arise from myeloid progenitors and suppress both innate and adaptive immunity. MDSCs expand during the later phases of sepsis in mice, promote immunosuppression, and reduce survival. Here, we report that the myeloid differentiation-related transcription factor nuclear factor I-A (NFI-A) controls MDSC expansion during sepsis and impacts survival. Unlike MDSCs, myeloid cells with conditional deletion of theNfiagene normally differentiated into effector cells during sepsis, cleared infecting bacteria, and did not express immunosuppressive mediators. In contrast, ectopic expression of NFI-A in myeloid progenitors from NFI-A myeloid cell-deficient mice impeded myeloid cell maturation and promoted immune repressor function. Importantly, surviving septic mice with conditionally deficient NFI-A myeloid cells were able to respond to challenge with bacterial endotoxin by mounting an acute inflammatory response. Together, these results support the concept of NFI-A as a master molecular transcriptome switch that controls myeloid cell differentiation and maturation and that malfunction of this switch during sepsis promotes MDSC expansion that adversely impacts sepsis outcome.
Department of Internal Medicine, East Tennessee State University College of Medicine, Johnson City, Tennessee, USA.
Melissa B
MB
McPeak
Department of Internal Medicine, East Tennessee State University College of Medicine, Johnson City, Tennessee, USA.
Dima
D
Youssef
Department of Health Sciences, East Tennessee State University College of Public Health, Johnson City, Tennessee, USA.
Danielle A
DA
Williams
Department of Health Sciences, East Tennessee State University College of Public Health, Johnson City, Tennessee, USA.
Christopher
C
Pritchett
Department of Internal Medicine, East Tennessee State University College of Medicine, Johnson City, Tennessee, USA.
Zhi Q
ZQ
Yao
Department of Internal Medicine, Section of Molecular Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.
Charles E
CE
McCall
Department of Internal Medicine, East Tennessee State University College of Medicine, Johnson City, Tennessee, USA elgazzar@etsu.edu.
Mohamed
M
El Gazzar
D000818:Animals; D015415:Biomarkers; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D018390:Gene Targeting; D005822:Genetic Vectors / Q000235:genetics; D007109:Immunity; D056747:Immunomodulation; D016130:Immunophenotyping; D007958:Leukocyte Count; D007962:Leukocytes / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism*; D000072737:Myeloid-Derived Suppressor Cells / Q000276:immunology / Q000378:metabolism; D051839:NFI Transcription Factors / Q000172:deficiency*; D010641:Phenotype; D018805:Sepsis / Q000235:genetics* / Q000276:immunology / Q000401:mortality*
D015415:Biomarkers; D016207:Cytokines; D008070:Lipopolysaccharides; D051839:NFI Transcription Factors
MDSCs; NFI-A; inflammation; sepsis; sepsis immunosuppression