Browsing by Subject "PU.1"

Now showing 1 - 3 of 3
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    PU.1 controls fibroblast polarization and tissue fibrosis
    (Springer Nature, 2019-02) Wohlfahrt, Thomas; Rauber, Simon; Uebe, Steffen; Luber, Markus; Soare, Alina; Ekici, Arif; Weber, Stefanie; Matei, Alexandru-Emil; Chen, Chih-Wei; Maier, Christiane; Karouzakis, Emmanuel; Kiener, Hans P.; Pachera, Elena; Dees, Clara; Beyer, Christian; Daniel, Christoph; Gelse, Kolja; Kremer, Andreas E.; Naschberger, Elisabeth; Stürzl, Michael; Butter, Falk; Sticherling, Michael; Finotto, Susetta; Kreuter, Alexander; Kaplan, Mark H.; Jüngel, Astrid; Gay, Steffen; Nutt, Stephen L.; Boykin, David W.; Poon, Gregory M. K.; Distler, Oliver; Schett, Georg; Distler, Jörg H. W.; Ramming, Andreas; Pediatrics, IU School of Medicine
    Fibroblasts are polymorphic cells with pleiotropic roles in organ morphogenesis, tissue homeostasis and immune responses. In fibrotic diseases, fibroblasts synthesize abundant amounts of extracellular matrix, which induces scarring and organ failure. By contrast, a hallmark feature of fibroblasts in arthritis is degradation of the extracellular matrix because of the release of metalloproteinases and degrading enzymes, and subsequent tissue destruction. The mechanisms that drive these functionally opposing pro-fibrotic and pro-inflammatory phenotypes of fibroblasts remain unknown. Here we identify the transcription factor PU.1 as an essential regulator of the pro-fibrotic gene expression program. The interplay between transcriptional and post-transcriptional mechanisms that normally control the expression of PU.1 expression is perturbed in various fibrotic diseases, resulting in the upregulation of PU.1, induction of fibrosis-associated gene sets and a phenotypic switch in extracellular matrix-producing pro-fibrotic fibroblasts. By contrast, pharmacological and genetic inactivation of PU.1 disrupts the fibrotic network and enables reprogramming of fibrotic fibroblasts into resting fibroblasts, leading to regression of fibrosis in several organs.
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    TH9 cells are required for tissue mast cell accumulation during allergic inflammation
    (Elsevier, 2015-08) Sehra, Sarita; Yao, Weiguo; Nguyen, Evelyn T.; Glossen-Byers, Nicole L.; Akhtar, Nahid; Zhou, Baohua; Kaplan, Mark H.; Department of Pediatrics, IU School of Medicine
    BACKGROUND: IL-9 is important for the growth and survival of mast cells. IL-9 is produced by T cells, natural killer T cells, mast cells, eosinophils, and innate lymphoid cells, although the cells required for mast cell accumulation during allergic inflammation remain undefined. OBJECTIVE: We sought to elucidate the role of TH9 cells in promoting mast cell accumulation in models of allergic lung inflammation. METHODS: Adoptive transfer of ovalbumin-specific TH2 and TH9 cells was used to assess the ability of each subset to mediate mast cell accumulation in tissues. Mast cell accumulation was assessed in wild-type mice and mice with PU.1-deficient T cells subjected to acute and chronic models of allergic inflammation. RESULTS: Adoptive transfer experiments demonstrated that recipients of TH9 cells had significantly higher mast cell accumulation and expression of mast cell proteases compared with control or TH2 recipients. Mast cell accumulation was dependent on IL-9, but not IL-13, a cytokine required for many aspects of allergic inflammation. In models of acute and chronic allergic inflammation, decreased IL-9 levels in mice with PU.1-deficient T cells corresponded to diminished tissue mast cell numbers and expression of mast cell proteases. Mice with PU.1-deficient T cells have defects in IL-9 production from CD4(+) T cells, but not natural killer T cells or innate lymphoid cells, suggesting a TH cell-dependent phenotype. Rag1(-/-) mice subjected to a chronic model of allergic inflammation displayed reduced mast cell infiltration comparable with accumulation in mice with PU.1-deficient T cells, emphasizing the importance of IL-9 produced by T cells in mast cell recruitment. CONCLUSION: TH9 cells are a major source of IL-9 in models of allergic inflammation and play an important role in mast cell accumulation and activation.
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    Transcription factor regulation of T helper subset function
    (2015-05-01) Awe, Olufolakemi O.; Kaplan, Mark H.; Blum, Janice S.; Zhou, Baohua; Travers, Jeffery B.
    The immune system protects the body from foreign organisms. T cells and B cells are integral components of the ability of the immune system to generate focused immune responses. The development of specialized subsets of T helper cells is governed by transcription factors. Previous work demonstrated a requirement for the transcription factor PU.1 in the development of IL-9-secreting Th9 cells. Work in this dissertation demonstrates that the Th9 subset is not stable in vitro, and that PU.1 expression decreases during long-term culture. To examine a role for PU.1 in Th9-independent immunity we examined a model of multiple sclerosis termed experimental autoimmune encephalomyelitis (EAE). Mice that lack PU.1 expression in T cells (Sfpi1lck-/- mice) demonstrated more severe disease with attenuated recovery compared to control mice, and this was accompanied by an increase of T cells in the central nervous system. We also observed that following multiple routes of immunization Sfpi1lck-/- mice had increased numbers of T follicular helper (Tfh) cells and increased germinal center responses. This correlated with increased expression of the cytokine IL-21 and the surface protein CD40L in T cells that lacked PU.1 expression and resulted in increased numbers of germinal center B cells and antigen-specific antibody titers compared to control mice. The increased germinal center B cells and antibody titers were attenuated with blocking CD40L antibody but not with neutralizing IL-21 antibody. These results suggest that PU.1 limits the expression of CD40L on Tfh cells to regulate the humoral immune response. Together, the data in this dissertation demonstrate Th9-independent functions of PU.1. Moreover, this work shows that transcription factors promoting the development of one subset of T helper cells can simultaneously have negative effects on distinct T cell lineages.