title: Perturbed MafB/GATA1 axis after burn trauma bares the potential mechanism for immune suppression and anemia of critical illness.
abstract: Patients who survive initial burn injury are susceptible to nosocomial infections. Anemia of critical illness is a compounding factor in burn patients that necessitates repeated transfusions, which further increase their susceptibility to infections and sepsis. Robust host response is dependent on an adequate number and function of monocytes/macrophages and dendritic cells. In addition to impaired RBC production, burn patients are prone to depletion of dendritic cells and an increase in deactivated monocytes. In steady-state hematopoiesis, RBCs, macrophages, and dendritic cells are all generated from a common myeloid progenitor within the bone marrow. We hypothesized in a mouse model of burn injury that an increase in myeloid-specific transcription factor V-maf musculoaponeurotic fibrosarcoma oncogene homolog B at the common myeloid progenitor stage steers their lineage potential away from the megakaryocyte erythrocyte progenitor production and drives the terminal fate of common myeloid progenitors to form macrophages vs. dendritic cells, with the consequences being anemia, monocytosis, and dendritic cell deficits. Results indicate that, even though burn injury stimulated bone marrow hematopoiesis by increasing multipotential stem cell production (LinnegSca1poscKitpos), the bone marrow commitment is shifted away from the megakaryocyte erythrocyte progenitor and toward granulocyte monocyte progenitors with corresponding alterations in peripheral blood components, such as hemoglobin, hematocrit, RBCs, monocytes, and granulocytes. Furthermore, burn-induced V-maf musculoaponeurotic fibrosarcoma oncogene homolog B in common myeloid progenitors acts as a transcriptional activator of M-CSFR and a repressor of transferrin receptors, promoting macrophages and inhibiting erythroid differentiations while dictating a plasmacytoid dendritic cell phenotype. Results from small interfering RNA and gain-of-function (gfp-globin transcription factor 1 retrovirus) studies indicate that targeted interventions to restore V-maf musculoaponeurotic fibrosarcoma oncogene homolog B/globin transcription factor 1 balance can mitigate both immune imbalance and anemia of critical illness.
authors.affiliation: Department of Surgery, Mount Sinai Hospital, Chicago, Illinois, USA.
authors.forename: Nicholas B
authors.initials: NB
authors.lastname: Johnson
authors.affiliation: Department of Surgery, Loyola University Medical Center, Maywood, Illinois, USA; Burn and Shock Trauma Research Institute, Loyola University Chicago, Chicago, Illinois, USA; and.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Posluszny
authors.affiliation: Department of Surgery, Loyola University Medical Center, Maywood, Illinois, USA; Burn and Shock Trauma Research Institute, Loyola University Chicago, Chicago, Illinois, USA; and.
authors.forename: Li K
authors.initials: LK
authors.lastname: He
authors.affiliation: Burn and Shock Trauma Research Institute, Loyola University Chicago, Chicago, Illinois, USA; and.
authors.forename: Andrea
authors.initials: A
authors.lastname: Szilagyi
authors.affiliation: Department of Surgery, Loyola University Medical Center, Maywood, Illinois, USA; Burn and Shock Trauma Research Institute, Loyola University Chicago, Chicago, Illinois, USA; and.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Gamelli
authors.affiliation: Department of Surgery, Loyola University Medical Center, Maywood, Illinois, USA; Burn and Shock Trauma Research Institute, Loyola University Chicago, Chicago, Illinois, USA; and.
authors.forename: Ravi
authors.initials: R
authors.lastname: Shankar
authors.affiliation: Department of Surgery, Loyola University Medical Center, Maywood, Illinois, USA; Burn and Shock Trauma Research Institute, Loyola University Chicago, Chicago, Illinois, USA; and kmuthu@luc.edu.
authors.forename: Kuzhali
authors.initials: K
authors.lastname: Muthumalaiappan
mesh_terms: D000740:Anemia / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology; D000818:Animals; D002056:Burns / Q000097:blood* / Q000235:genetics / Q000276:immunology*; D019070:Cell Lineage; D002478:Cells, Cultured; D016638:Critical Illness; D003713:Dendritic Cells / Q000473:pathology; D050982:GATA1 Transcription Factor / Q000235:genetics / Q000502:physiology*; D008264:Macrophages / Q000473:pathology; D051258:MafB Transcription Factor / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D009000:Monocytes / Q000473:pathology; D023461:Myeloid Progenitor Cells / Q000473:pathology*; D038042:Myelopoiesis / Q000235:genetics*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000096:biosynthesis / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D050982:GATA1 Transcription Factor; C494689:Gata1 protein, mouse; D051258:MafB Transcription Factor; C490406:Mafb protein, mouse; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D016186:Receptor, Macrophage Colony-Stimulating Factor
keywords: CMP; MEP; dendritic cell; hematopoiesis; macrophages