Deficiency of KLF4 compromises the lung function in an acute mouse model of allergic asthma.

Abstract

Asthma is a chronic inflammatory disease of the airways and the mechanisms are not fully understood. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of monocytes, granulocyte and myeloid cells at early stage of differentiation. They possess phenotypic plasticity and regulate airway inflammation. We recently reported that Kruppel-like factor 4 (KLF4) regulates MDSC differentiation into fibrocytes, emerging effectors in chronic inflammation. However, the role of KLF4 in asthma is not known. Thymic stromal lymphopoietin (TSLP) is an epithelial cell-derived cytokine and a key initiator of allergic airway inflammation. Given the fact that TSLP promotes Th2 cytokine production that increases MDSC differentiation into fibrocytes, we postulate that KLF4 regulates asthma in a TSLP-dependent manner. In this study, we utilized a model of allergic asthma with ovalbumin challenge (OVA). We found that upon OVA treatment the wild type mice had increased MDSC infiltration into the lung, up-regulation of KLF4 and TSLP gene expression, and higher levels of Th2 cytokines including IL4 and IL13. Consistently, lack of KLF4 expression in monocytes and lung epithelial cells resulted in decreased TSLP expression and lower levels of Th2 cytokines in mice, and fibrocyte generation was compromised. KLF4 deficiency in these cells also led to decreased airway hyperresponsiveness (AHR), a cardinal feature of asthma, as assessed by whole body plethysmography. Moreover, lung fibrosis as measured by trichome staining was attenuated and the population of CD45 + COL1A1+ fibrocytes was diminished in this setting. Together, our results suggest that KLF4 regulates asthma development in a TSLP- and fibrocyte-dependent manner.

• Authors: Jeanette A Nimpong, Wintana Gebregziabher, Udai P Singh, Prakash Nagarkatti, Mitzi Nagarkatti, Johnie Hodge, Chunming Liu, Daping Fan, Walden Ai
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 493 Issue 1 Pg. 598-603 (11 04 2017) ISSN: 1090-2104 [Electronic] United States
• PMID: 28867182 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 Elsevier Inc. All rights reserved.

Chemical References

• Cytokines
• Klf4 protein, mouse
• Kruppel-Like Factor 4
• Kruppel-Like Transcription Factors
• trypsin-like serine protease
• Serine Endopeptidases

Topics

• Acute Disease
• Animals
• Asthma (pathology, physiopathology)
• Cytokines (immunology)
• Kruppel-Like Factor 4
• Kruppel-Like Transcription Factors (immunology)
• Lung (pathology, physiopathology)
• Male
• Mice
• Mice, Inbred C57BL
• Myeloid-Derived Suppressor Cells (immunology, pathology)
• Serine Endopeptidases (immunology)