title: The transcription factor PU.1 promotes alternative macrophage polarization and asthmatic airway inflammation.
abstract: The transcription factor PU.1 is involved in regulation of macrophage differentiation and maturation. However, the role of PU.1 in alternatively activated macrophage (AAM) and asthmatic inflammation has yet been investigated. Here we report that PU.1 serves as a critical regulator of AAM polarization and promotes the pathological progress of asthmatic airway inflammation. In response to the challenge of DRA (dust mite, ragweed, and Aspergillus) allergens, conditional PU.1-deficient (PU/ER(T)(+/-)) mice displayed attenuated allergic airway inflammation, including decreased alveolar eosinophil infiltration and reduced production of IgE, which were associated with decreased mucous glands and goblet cell hyperplasia. The reduced asthmatic inflammation in PU/ER(T)(+/-) mice was restored by adoptive transfer of IL-4-induced wild-type (WT) macrophages. Moreover, after treating PU/ER(T)(+/-) mice with tamoxifen to rescue PU.1 function, the allergic asthmatic inflammation was significantly restored. In vitro studies demonstrate that treatment of PU.1-deficient macrophages with IL-4 attenuated the expression of chitinase 3-like 3 (Ym-1) and resistin-like molecule alpha 1 (Fizz-1), two specific markers of AAM polarization. In addition, PU.1 expression in macrophages was inducible in response to IL-4 challenge, which was associated with phosphorylation of signal transducer and activator of transcription 6 (STAT6). Furthermore, DRA challenge in sensitized mice almost abrogated gene expression of Ym-1 and Fizz-1 in lung tissues of PU/ER(T)(+/-) mice compared with WT mice. These data, all together, indicate that PU.1 plays a critical role in AAM polarization and asthmatic inflammation.
authors.affiliation: School of Pharmacy, Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China Department of Internal Medicine, Section of Pulmonary, Allergy, Critical Care, and Sleep Medicine, The Ohio State University, Columbus, USA john.christman@osumc.edu fengqian7@outlook.com.
authors.forename: Feng
authors.initials: F
authors.lastname: Qian
authors.affiliation: Department of Internal Medicine, Section of Pulmonary, Allergy, Critical Care, and Sleep Medicine, The Ohio State University, Columbus, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Deng
authors.affiliation: Department of Internal Medicine, Section of Pulmonary, Allergy, Critical Care, and Sleep Medicine, The Ohio State University, Columbus, USA.
authors.forename: Yong Gyu
authors.initials: YG
authors.lastname: Lee
authors.affiliation: Department of Physiology and Biophysics, College of Medicine, University of Illinois at Chicago, Chicago, USA.
authors.forename: Jimmy
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Department of Internal Medicine, Section of Pulmonary, Allergy, Critical Care, and Sleep Medicine, The Ohio State University, Columbus, USA.
authors.forename: Manjula
authors.initials: M
authors.lastname: Karpurapu
authors.affiliation: Department of Internal Medicine, Section of Pulmonary, Allergy, Critical Care, and Sleep Medicine, The Ohio State University, Columbus, USA.
authors.forename: Sangwoon
authors.initials: S
authors.lastname: Chung
authors.affiliation: Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical College, Xuzhou, China.
authors.forename: Jun-Nian
authors.initials: JN
authors.lastname: Zheng
authors.affiliation: Department of Medicine, Section of Pulmonary, Critical Care, and Sleep Medicine, University of Illinois at Chicago, Chicago, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Xiao
authors.affiliation: Department of Medicine, Section of Pulmonary, Critical Care, and Sleep Medicine, University of Illinois at Chicago, Chicago, USA.
authors.forename: Gye Young
authors.initials: GY
authors.lastname: Park
authors.affiliation: Department of Internal Medicine, Section of Pulmonary, Allergy, Critical Care, and Sleep Medicine, The Ohio State University, Columbus, USA john.christman@osumc.edu fengqian7@outlook.com.
authors.forename: John W
authors.initials: JW
authors.lastname: Christman
mesh_terms: D019264:Adoptive Transfer; D000485:Allergens / Q000276:immunology; D000818:Animals; D001249:Asthma / Q000276:immunology* / Q000473:pathology*; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D004804:Eosinophils / Q000276:immunology; D006967:Hypersensitivity / Q000276:immunology; D007249:Inflammation / Q000276:immunology; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D015847:Interleukin-4 / Q000276:immunology; D037102:Lectins / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000473:pathology; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000276:immunology*; D011650:Pulmonary Alveoli / Q000166:cytology; D018418:Th2 Cells / Q000276:immunology; D015534:Trans-Activators / Q000235:genetics / Q000276:immunology*; D001619:beta-N-Acetylhexosaminidases / Q000378:metabolism; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D000485:Allergens; D036341:Intercellular Signaling Peptides and Proteins; D015847:Interleukin-4; D037102:Lectins; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D001619:beta-N-Acetylhexosaminidases; D000099232:Proto-Oncogene Protein Spi-1; C413576:Retnla protein, mouse; C429541:Chil3 protein, mouse
keywords: IL-4; PU.1; Th2; alternatively activated macrophage; asthmatic inflammation