Asthma is characterized by chronic inflammation of the airways, causing recurrent wheezing, dyspnea, chest tightness, and cough, while inflammation in airway epithelial cells is closely related to asthma (Mims, 2015). The airway epithelial cells lie at the interface between the internal and external environment, and the damage of airway epithelial cells and the destruction of the epithelial barrier may lead to asthma-related airway inflammation (Gon and Hashimoto, 2018). Pyroptosis refers to the formation of pores in the cell membrane and the continuous expansion of the cell to rupture, causing the release of inflammatory factors into the extracellular space, which leads to intense inflammation (Liu et al., 2023b). Pyroptosis may induce asthma by destroying the integrity of epithelial cells, leading to the recruitment of inflammatory cells and allergens (Feng et al., 2022). Moreover, epithelial damage-induced pyroptosis impairs the ability of epithelial cells to provide mucociliary clearance, allowing various allergens to affect the lungs (Feng et al., 2022). The persistent inflammatory stimulus triggered by pyroptosis may lead to airway remodeling, which is an important pathogenic feature of asthma (Sun and Li, 2022). Herein, inhibition of pyroptosis is a potential target for the treatment of respiratory diseases, including asthma (Feng et al., 2022). Therefore, we established the mouse model of asthma to explore its potential mechanism and provide a possible scheme for the treatment of asthma.

The kruppel-like factor (KLF) family is a group of evolutionarily conserved zinc-finger transcription factors associated with specific proteins involved in cell development (Palioura et al., 2022). As a member of the KLF family, KLF5 regulates various cellular functions including apoptosis, proliferation, and differentiation (Li et al., 2021). A previous study has shown that ovalbumin (OVA) induction can increase the transcriptional activity of KLF5, which in turn increases the level of inflammatory factors in bronchial epithelial cells and induces inflammation (Wei et al., 2021). KLF5 activates the NF-κB pathway to promote lung cell injury in bronchopulmonary dysplasia (Meng et al., 2022). In addition, KLF5 may play a role in inducing pyroptosis (Rozi et al., 2022), but whether KLF5 participates in asthma through pyroptosis remains unclear.

MicroRNAs (miRs) are small non-coding RNA molecules that repress gene expression by suppressing protein translation and supporting mRNA cleavage, leading to a variety of human diseases (Ho et al., 2022). In asthma, alterations in miRs lead to airway hyperresponsiveness and disrupt epithelial cells and normal immune response regulation, resulting in airway inflammation and allergic reactions (Weidner et al., 2021). Importantly, miRs play a role in slowing down inflammatory response, inhibiting airway hyperresponsiveness, reducing oxidative stress and mitochondrial damage to inhibit epithelial cell inflammation in asthmatic mice, such as miR-493–5p (Rao et al., 2022), miR-138 (Huang et al., 2017), and miR-182–5p (Wang et al., 2022b). Current evidence has shown that overexpression of miR-182–5p not only inhibits the excessive inflammation caused by acute lung injury (Zhu et al., 2018) but also ameliorates pulmonary fibrosis (Xiao et al., 2020). Interestingly, the JASPAR database predicted that KLF5 had a binding site with miR-182–5p, and our study verified the binding relationship between KLF5 and miR-182–5p, which may be a potential pathway for asthma treatment.

Toll-like receptor 4 (TLR4) is a member of the TLR family, whose excessive activation could produce inflammatory factors (Zhang et al., 2022). It has been demonstrated that TLR4 can promote the activation of NLR family pyrin domain containing 3 (NLRP3) inflammasome to mediate microglial pyroptosis in spinal cord injury (Wang et al., 2022a). TLR4 expression is increased in OVA-induced asthmatic mice and plays a role in promoting pyroptosis and the release of inflammatory factors (Liu et al., 2023a). Since TLR4 is involved in the regulation of pyroptosis-related proteins, targeting TLR4 to alleviate airway inflammation, airway hyperresponsiveness, airway remodeling, and pyroptosis in airway epithelial cells has been proven to be a potential asthma treatment (Lyu et al., 2023).

In our study, we established the asthma mouse model to explore the molecular mechanism of KLF5 in regulating asthmatic airway inflammation by mediating pyroptosis through the miR-182–5p/TLR4 axis, so as to provide a potential option for asthma treatment.