title: Prevention of bone marrow cell apoptosis and regulation of hematopoiesis by type I IFNs during systemic responses to pneumocystis lung infection.
abstract: We recently demonstrated that lack of type I IFN signaling (IFNAR knockout) in lymphocyte-deficient mice (IFrag(-/-)) results in bone marrow (BM) failure after Pneumocystis lung infection, whereas lymphocyte-deficient mice with intact IFNAR (RAG(-/-)) had normal hematopoiesis. In the current work, we performed studies to define further the mechanisms involved in the induction of BM failure in this system. BM chimera experiments revealed that IFNAR expression was required on BM-derived but not stroma-derived cells to prevent BM failure. Signals elicited after day 7 postinfection appeared critical in determining BM cell fate. We observed caspase-8- and caspase-9-mediated apoptotic cell death, beginning with neutrophils. Death of myeloid precursors was associated with secondary oxidative stress, and decreasing colony-forming activity in BM cell cultures. Treatment with N-acetylcysteine could slow the progression of, but not prevent, BM failure. Type I IFN signaling has previously been shown to expand the neutrophil life span and regulate the expression of some antiapoptotic factors. Quantitative RT-PCR demonstrated reduced mRNA abundance for the antiapoptotic factors BCL-2, IAP2, MCL-1, and others in BM cells from IFrag(-/-) compared with that in BM cells from RAG(-/-) mice at day 7. mRNA and protein for the proapoptotic cytokine TNF-α was increased, whereas mRNA for the growth factors G-CSF and GM-CSF was reduced. In vivo anti-TNF-α treatment improved precursor cell survival and activity in culture. Thus, we propose that lack of type I IFN signaling results in decreased resistance to inflammation-induced proapoptotic stressors and impaired replenishment by precursors after systemic responses to Pneumocystis lung infection. Our finding may have implications in understanding mechanisms underlying regenerative BM depression/failure during complex immune deficiencies such as AIDS.
authors.affiliation: Department of Immunology and Infectious Diseases, Montana State University, Bozeman, MT 59718, USA.
authors.forename: David
authors.initials: D
authors.lastname: Taylor
authors.forename: Michelle
authors.initials: M
authors.lastname: Wilkison
authors.forename: Jovanka
authors.initials: J
authors.lastname: Voyich
authors.forename: Nicole
authors.initials: N
authors.lastname: Meissner
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D001854:Bone Marrow Cells / Q000378:metabolism / Q000502:physiology*; D053181:Caspase 8 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D016654:Genes, RAG-1; D019254:Genes, bcl-2; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics; D006410:Hematopoiesis; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics; D007370:Interferon Type I / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D008969:Molecular Sequence Data; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D023461:Myeloid Progenitor Cells / Q000276:immunology; D009504:Neutrophils / Q000276:immunology; D018384:Oxidative Stress; D011010:Pneumocystis / Q000276:immunology* / Q000472:pathogenicity; D011020:Pneumonia, Pneumocystis / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology*; D016133:Polymerase Chain Reaction; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D011828:Radiation Chimera; D053633:Receptor, Interferon alpha-beta / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D044767:Ubiquitin-Protein Ligases
chemical_list: C508034:Ifnar2 protein, mouse; D051034:Inhibitor of Apoptosis Proteins; D007370:Interferon Type I; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D053633:Receptor, Interferon alpha-beta; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; C494835:Birc3 protein, mouse; D044767:Ubiquitin-Protein Ligases; D053181:Caspase 8; D053453:Caspase 9; D000111:Acetylcysteine