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.

MiR-135-5p-p62 Axis Regulates Autophagic Flux, Tumorigenic Potential, and Cellular Interactions Mediated by Extracellular Vesicles During Allergic Inflammation

“…Intravitreal application of miR-135 facilitates retinal ganglion cell (RGC) axon regeneration after optic nerve injury in adult mice in part by repressing KLF4 (44). Lack of Kruppel-like factor 4 (KLF4) expression in monocytes and lung epithelial cells decreases Th2 cytokines in mice and airway hyper responsiveness (AHR) (45). Endogenous KLF4 can bind to promoter regions of p62 gene while upregulation of KLF4 induces expression of p62 (46).…”

The SOD Mimic, MnTE-2-PyP, Protects from Chronic Fibrosis and Inflammation in Irradiated Normal Pelvic Tissues

“…A higher expression of Th2 cytokines and a reduction of Th1 cytokine production has been reported after radiation exposure and other fibrotic disorders. Specifically, Th2 cytokines IL-4 and IL-5 have been found to be upregulated during fibrosis [ 20 , 21 , 22 , 23 , 24 ]. However, Th17 cells do not appear to be affected by radiation exposure.…”

Putative regulatory functions of SNPs associated with bronchial asthma, arterial hypertension and their comorbid phenotype

“…The C allele of rs1980616 of SERPINA1 gene is associ ated with an increase in the affinity of TF Klf4 involved in inflammatory reactions, airway remodeling, and control of Th2-type cellular response (Tussiwand et al, 2015). In mice, in suppressor cells of myeloid origin and in epithelial cells of the respiratory tract, after exposure to the allergen, Putative regulatory functions of SNPs associated with bronchial asthma, arterial hypertension and their comorbid phenotype Klf4 gene expression increased in the direct proportion to the severity of allergic asthma (Nimpong et al, 2017). Among the other va riants studied in this study, rs1980616 has the highest regulatory potential with the rank of 2b and the scale of 0.83 (see Table 2).…”