Browsing by Author "Yang, Shuangshuang"

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    An IL-9-pulmonary macrophage axis defines the allergic lung inflammatory environment
    (American Association for the Advancement of Science, 2022) Fu, Yongyao; Wang, Jocelyn; Zhou, Baohua; Pajulas, Abigail; Gao, Hongyu; Ramdas, Baskar; Koh, Byunghee; Ulrich, Benjamin J.; Yang, Shuangshuang; Kapur, Reuben; Renauld, Jean-Christophe; Paczesny, Sophie; Liu, Yunlong; Tighe, Robert M.; Licona-Limón, Paula; Flavell, Richard A.; Takatsuka, Shogo; Kitamura, Daisuke; Tepper, Robert S.; Sun, Jie; Kaplan, Mark H.; Microbiology and Immunology, School of Medicine
    Despite IL-9 functioning as a pleiotropic cytokine in mucosal environments, the IL-9-responsive cell repertoire is still not well defined. Here, we found that IL-9 mediates proallergic activities in the lungs by targeting lung macrophages. IL-9 inhibits alveolar macrophage expansion and promotes recruitment of monocytes that develop into CD11c+ and CD11c- interstitial macrophage populations. Interstitial macrophages were required for IL-9-dependent allergic responses. Mechanistically, IL-9 affected the function of lung macrophages by inducing Arg1 activity. Compared with Arg1-deficient lung macrophages, Arg1-expressing macrophages expressed greater amounts of CCL5. Adoptive transfer of Arg1+ lung macrophages but not Arg1- lung macrophages promoted allergic inflammation that Il9r-/- mice were protected against. In parallel, the elevated expression of IL-9, IL-9R, Arg1, and CCL5 was correlated with disease in patients with asthma. Thus, our study uncovers an IL-9/macrophage/Arg1 axis as a potential therapeutic target for allergic airway inflammation.
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    FOXP3 exon 2 controls Treg stability and autoimmunity
    (American Association for the Advancement of Science, 2022) Du, Jianguang; Wang, Qun; Yang, Shuangshuang; Chen, Si; Fu, Yongyao; Spath, Sabine; Domeier, Phillip; Hagin, David; Anover-Sombke, Stephanie; Haouili, Maya; Liu, Sheng; Wan, Jun; Han, Lei; Liu, Juli; Yang, Lei; Sangani, Neel; Li, Yujing; Lu, Xiongbin; Janga, Sarath Chandra; Kaplan, Mark H.; Torgerson, Troy R.; Ziegler, Steven F.; Zhou, Baohua; Pediatrics, School of Medicine
    Differing from the mouse Foxp3 gene that encodes only one protein product, human FOXP3 encodes two major isoforms through alternative splicing-a longer isoform (FOXP3 FL) containing all the coding exons and a shorter isoform lacking the amino acids encoded by exon 2 (FOXP3 ΔE2). The two isoforms are naturally expressed in humans, yet their differences in controlling regulatory T cell phenotype and functionality remain unclear. In this study, we show that patients expressing only the shorter isoform fail to maintain self-tolerance and develop immunodeficiency, polyendocrinopathy, and enteropathy X-linked (IPEX) syndrome. Mice with Foxp3 exon 2 deletion have excessive follicular helper T (TFH) and germinal center B (GC B) cell responses, and develop systemic autoimmune disease with anti-dsDNA and antinuclear autoantibody production, as well as immune complex glomerulonephritis. Despite having normal suppressive function in in vitro assays, regulatory T cells expressing FOXP3 ΔE2 are unstable and sufficient to induce autoimmunity when transferred into Tcrb-deficient mice. Mechanistically, the FOXP3 ΔE2 isoform allows increased expression of selected cytokines, but decreased expression of a set of positive regulators of Foxp3 without altered binding to these gene loci. These findings uncover indispensable functions of the FOXP3 exon 2 region, highlighting a role in regulating a transcriptional program that maintains Treg stability and immune homeostasis.
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    NMP4 regulates the innate immune response to influenza A virus infection
    (Springer Nature, 2021-01) Yang, Shuangshuang; Adaway, Michele; Du, Jianguang; Huang, Shengping; Sun, Jie; Bidwell, Joseph P.; Zhou, Baohua; Pediatrics, School of Medicine
    Severe influenza A virus infection typically triggers excessive and detrimental lung inflammation with massive cell infiltration and hyper-production of cytokines and chemokines. We identified a novel function for nuclear matrix protein 4 (NMP4), a zinc-finger-containing transcription factor playing roles in bone formation and spermatogenesis, in regulating antiviral immune response and immunopathology. Nmp4-deficient mice are protected from H1N1 influenza infection, losing only 5% body weight compared to a 20% weight loss in wild type mice. While having no effects on viral clearance or CD8/CD4 T cell or humoral responses, deficiency of Nmp4 in either lung structural cells or hematopoietic cells significantly reduces the recruitment of monocytes and neutrophils to the lungs. Consistent with fewer innate cells in the airways, influenza-infected Nmp4-deficient mice have significantly decreased expression of chemokine genes Ccl2, Ccl7 and Cxcl1 as well as pro-inflammatory cytokine genes Il1b and Il6. Furthermore, NMP4 binds to the promoters and/or conserved non-coding sequences of the chemokine genes and regulates their expression in mouse lung epithelial cells and macrophages. Our data suggest that NMP4 functions to promote monocyte- and neutrophil-attracting chemokine expression upon influenza A infection, resulting in exaggerated innate inflammation and lung tissue damage.
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    Roles of Transcription Factors NMP4 and FOXP3 in Regulating Airway Inflammation
    (2020-08) Yang, Shuangshuang; Zhou, Baohua; Kaplan, Mark H.; Blum, Janice S.; Harrington, Maureen A.
    Airway inflammation is the most common and important component of respiratory diseases, such as influenza and asthma. Severe influenza A virus infection typically triggers detrimental lung inflammation with massive immune cell infiltration and hyper-production of cytokines and chemokines. We identified a novel function for nuclear matrix protein 4 (NMP4), a zinc-finger-containing transcription factor known for its function in bone formation and spermatogenesis, in regulating antiviral immune responses and immunopathology. Nmp4-deficient mice are protected from influenza induced immunopathology and body weight loss. While having no effects on viral clearance or CD8/CD4 T cell or humoral immune responses, Nmp4 deficiency in either lung structural cells or hematopoietic cells significantly reduces the recruitment of neutrophils and monocytes to the lungs. Furthermore, NMP4 binds to the promoters and/or conserved non-coding sequences of the chemokine genes Ccl2 and Cxcl1 and upregulates their expression in mouse lung epithelial cells and macrophages. These chemokines attract monocytes and neutrophils to the airway, resulting in exaggerated airway inflammation and collateral lung damage. Another transcription factor forkhead box P3 (FOXP3) is critical for the development of regulatory T cells (Tregs) that function to control immune responses. Unlike human FOXP3 gene that encodes two major isoforms, a full length (FOXP3-FL) isoform and a short isoform lacking the exon 2 region (FOXP3-ΔE2), mouse Foxp3 gene only encodes Foxp3-FL isoform. We generate Foxp3-ΔE2 mice to study its function and find that Tregs expressing the Foxp3-ΔE2 isoform have intrinsic defects, thus allowing intensified adaptive immune responses without changes in innate immunity against influenza infection. In a model of chronic asthma, mice expressing only the Foxp3-ΔE2 isoform have significantly increased allergic airway inflammation and elevated production of allergen-specific IgE compared with mice expression the Foxp3-FL isoform. Mechanistically, Tregs expressing the Foxp3-ΔE2 isoform are less stable and prone to trans-differentiation into effector Th9-like cells, which are closely associated with the pathogenesis of asthma. These data suggest that the two Foxp3 isoforms have different functions in regulating airway immune responses. Overall, we have defined the important roles of both transcription factors NMP4 and FOXP3 in regulating airway inflammation.