title: Functional PU.1 in macrophages has a pivotal role in NF-κB activation and neutrophilic lung inflammation during endotoxemia.
abstract: Although the role of ETS family transcriptional factor PU.1 is well established in macrophage maturation, its role in mature macrophages with reference to sepsis- related animal model has not been elucidated. Here, we report the in vivo function of PU.1 in mediating mature macrophage inflammatory phenotype by using bone marrow chimera mice with conditional PU.1 knockout. We observed that the expression of monocyte/macrophage-specific markers CD 11b, F4/80 in fetal liver cells, and bone marrow-derived macrophages were dependent on functional PU.1. Systemic inflammation as measured in terms of NF-κB reporter activity in lung, liver, and spleen tissues was significantly decreased in PU.1-deficient chimera mice compared with wild-type chimeras on lipopolysaccharide (LPS) challenge. Unlike wild-type chimera mice, LPS challenge in PU.1-deficient chimera mice resulted in decreased lung neu-trophilic inflammation and myeloperoxidase activity. Similarly, we found attenuated inflammatory gene expression (cyclooxygenase-2, inducible nitric-oxide synthase, and TLR4) and inflammatory cytokine secretion (IL-6, MCP-1, IL-1β, TNF-α, and neutrophilic chemokine keratinocyte-derived chemokine) in PU.1-deficient mice. Most importantly, this attenuated lung and systemic inflammatory phenotype was associated with survival benefit in LPS-challenged heterozygotic PU.1-deficient mice, establishing a novel protective mechanistic role for the lineage-specific transcription factor PU.1.
authors.affiliation: Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, University of Illinois, Chicago, 60612, USA.
authors.forename: Manjula
authors.initials: M
authors.lastname: Karpurapu
authors.forename: Xuerong
authors.initials: X
authors.lastname: Wang
authors.forename: Jing
authors.initials: J
authors.lastname: Deng
authors.forename: Hyesuk
authors.initials: H
authors.lastname: Park
authors.forename: Lei
authors.initials: L
authors.lastname: Xiao
authors.forename: Ruxana T
authors.initials: RT
authors.lastname: Sadikot
authors.forename: Randall S
authors.initials: RS
authors.lastname: Frey
authors.forename: Ulrich A
authors.initials: UA
authors.lastname: Maus
authors.forename: Gye Young
authors.initials: GY
authors.lastname: Park
authors.forename: Edward W
authors.initials: EW
authors.lastname: Scott
authors.forename: John W
authors.initials: JW
authors.lastname: Christman
mesh_terms: D000818:Animals; D019446:Endotoxemia / Q000378:metabolism* / Q000473:pathology; D016130:Immunophenotyping; D008070:Lipopolysaccharides / Q000633:toxicity; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism*; D009504:Neutrophils / Q000473:pathology; D011014:Pneumonia / Q000378:metabolism / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D018183:Transplantation Chimera; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D008070:Lipopolysaccharides; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1