The critical role of epithelial-derived Act1 in IL-17- and IL-25-mediated pulmonary inflammation.

  • Swaidani S
  • Bulek K
  • Kang Z
 et al. 
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Abstract

IL-25 initiates, promotes, and augments Th2 immune responses. In this study, we report that Act1, a key component in IL-17-mediated signaling, is an essential signaling molecule for IL-25 signaling. Although Act1-deficient mice showed reduced expression of KC (CXCL1) and neutrophil recruitment to the airway compared with wild-type mice in response to IL-17 stimulation, Act1 deficiency abolished IL-25-induced expression of IL-4, IL-5, IL-13, eotaxin-1 (CCL11), and pulmonary eosinophilia. Using a mouse model of allergic pulmonary inflammation, we observed diminished Th2 responses and lung inflammation in Act1-deficient mice compared with wild-type mice. Importantly, Act1 deficiency in epithelial cells reduced the phenotype of allergic pulmonary inflammation due to loss of IL-17-induced neutrophilia and IL-25-induced eosinophilia, respectively. These results demonstrate the essential role of epithelial-derived Act1 in allergic pulmonary inflammation through the distinct impact of the IL-17R-Act1 and IL-25R-Act1 axes. Such findings are crucial for the understanding of pathobiology of atopic diseases, including allergic asthma, which identifies Act1 as a potential therapeutic target.

Author-supplied keywords

  • Adaptor Proteins, Signal Transducing
  • Adaptor Proteins, Signal Transducing: deficiency
  • Adaptor Proteins, Signal Transducing: genetics
  • Adaptor Proteins, Signal Transducing: physiology
  • Animals
  • Bronchoalveolar Lavage Fluid
  • Bronchoalveolar Lavage Fluid: cytology
  • Bronchoalveolar Lavage Fluid: immunology
  • Cells, Cultured
  • Eosinophilia
  • Eosinophilia: immunology
  • Eosinophilia: metabolism
  • Eosinophilia: prevention & control
  • Female
  • HeLa Cells
  • Humans
  • Inflammation Mediators
  • Inflammation Mediators: physiology
  • Interleukin-17
  • Interleukin-17: administration & dosage
  • Interleukin-17: physiology
  • Interleukins
  • Interleukins: administration & dosage
  • Interleukins: physiology
  • Lung
  • Lung: immunology
  • Lung: metabolism
  • Lung: pathology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Respiratory Hypersensitivity
  • Respiratory Hypersensitivity: immunology
  • Respiratory Hypersensitivity: metabolism
  • Respiratory Hypersensitivity: pathology
  • Respiratory Mucosa
  • Respiratory Mucosa: immunology
  • Respiratory Mucosa: metabolism
  • Respiratory Mucosa: pathology

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Authors

  • Shadi Swaidani

  • Katarzyna Bulek

  • Zizhen Kang

  • Caini Liu

  • Yi Lu

  • Weiguo Yin

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