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: Feng Qian, Jing Deng, Yong Gyu Lee, Jimmy Zhu, Manjula Karpurapu, Sangwoon Chung, Jun-Nian Zheng, Lei Xiao, Gye Young Park, John W Christman
• Journal: Journal of molecular cell biology (J Mol Cell Biol) Vol. 7 Issue 6 Pg. 557-67 (Dec 2015) ISSN: 1759-4685 [Electronic] United States
• PMID: 26101328 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © The Author (2015). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS. All rights reserved.

Chemical References

• Allergens
• Intercellular Signaling Peptides and Proteins
• Lectins
• Proto-Oncogene Proteins
• Retnla protein, mouse
• Trans-Activators
• proto-oncogene protein Spi-1
• Interleukin-4
• Chil3 protein, mouse
• beta-N-Acetylhexosaminidases

Topics

• Adoptive Transfer
• Allergens (immunology)
• Animals
• Asthma (immunology, pathology)
• Chemotaxis, Leukocyte (immunology)
• Eosinophils (immunology)
• Hypersensitivity (immunology)
• Inflammation (immunology)
• Intercellular Signaling Peptides and Proteins (metabolism)
• Interleukin-4 (immunology)
• Lectins (metabolism)
• Lung (immunology, pathology)
• Macrophage Activation
• Macrophages (immunology)
• Mice
• Mice, Transgenic
• Proto-Oncogene Proteins (genetics, immunology)
• Pulmonary Alveoli (cytology)
• Th2 Cells (immunology)
• Trans-Activators (genetics, immunology)
• beta-N-Acetylhexosaminidases (metabolism)