Exosomes have emerged as a vital player in cell-cell communication; however, whether airway epithelial cells (AECs) generated exosomes participate in asthma development remains unknown. To characterize the AECs-secreted exosomes and the potentially functional protein(s) that may contribute to the proinflammatory effects of AECs exosomes in the dendritic cells (DCs)-dominant airway allergic models, and confirming their clinical significance in asthmatic patients. Mice were treated with exosomes derived from house dust mite (HDM)-stimulated AECs (HDM-AECs-EXO) or monocyte-derived DCs (moDCs) primed by HDM and/or contactin-1 (CNTN1). Numbers of DCs in the lung were determined by flow cytometry (FCM). Proteomic analysis of purified HDM-AECs-EXO was performed. CNTN1-siRNA was designed to probe its role in airway allergy, and γ-secretase inhibitor (GSI) was used to determine the involvement of the Notch pathway. HDM-AECs-EXO facilitates the recruitment, proliferation, migration and activation of moDCs in cell culture and in mice. CNTN1 in exosomes is a critical player in asthma pathology. RNAi-mediated silencing and pharmaceutical inhibitors characterize Notch2 receptor as necessity for relaying the CNTN1 signal to activate Th2/Th17 immune response. Studies of asthmatic patients also support the CNTN1-Notch2 axis observed in cell and mouse models. These findings uncover a novel role for CNTN1 in asthmatic pathogenesis mediated through exosomes secretion, indicating a potential strategy for the treatment of allergic airway inflammation.

Asthma is thought to be caused by malfunction of type 2 T helper cell (Th2)-mediated immunity, causing excessive inflammation, mucus overproduction, and apoptosis of airway epithelial cells. Heme oxygenase-1 (HO-1) functions in heme catabolism and is both cytoprotective and anti-inflammatory. We hypothesized that this dual function may be related to asthma’s etiology. Using primary airway epithelial cells (pAECs) and an asthma mouse model, we demonstrate that severe lung inflammation is associated with rapid pAEC apoptosis. Surprisingly, NOD-like receptor protein 3 (NLRP3) inhibition, retinoid X receptor (RXR) deficiency, and HO-1 induction were associated with abrogated apoptosis. MCC950, a selective small-molecule inhibitor of canonical and noncanonical NLRP3 activation, reduced RXR expression, leading to decreased pAEC apoptosis that was reversed by the RXR agonist adapalene. Of note, HO-1 induction in a mouse model of ovalbumin-induced eosinophilic asthma suppressed Th2 responses and reduced apoptosis of pulmonary pAECs. In vitro, HO-1 induction desensitized cultured pAECs to ovalbumin-induced apoptosis, confirming the in vivo observations. Critically, the HO-1 products carbon monoxide and bilirubin suppressed the NLRP3–RXR axis in pAECs. Furthermore, HO-1 impaired production of NLRP3-RXR–induced cytokines (interleukin [IL]-25, IL-33, thymic stromal lymphopoietin [TSLP] and granulocyte-macrophage colony-stimulating factor [GM-SCF]) in pAECs and lungs. Finally, we demonstrate that HO-1 binds to the NACHT domain of NLRP3 and the RXRα and RXRβ subunits and that this binding is not reversed by Sn-protoporphyrin. Our findings indicate that HO-1 and its products are essential for pAEC survival to maintain airway epithelium homeostasis during NLRP3-RXR–mediated apoptosis and inflammation.

Pseudomonas aeruginosa ( P. aeruginosa ) is an opportunistic Gram-negative bacterium that causes severe infection in immune-weakened individuals, especially patients with cystic fibrosis, burn wounds, cancer, or chronic obstructive pulmonary disease (COPD). Treating P. aeruginosa infection with conventional antibiotics is difficult due to its intrinsic multidrug resistance.

Epithelial cells (ECs)‐derived cytokines are induced by different stimuli through pattern recognition receptors (PRRs) to mount a type‐2‐cell‐mediated immune response; however, the underlying mechanisms are poorly characterized. Here, we demonstrated asthmatic features in both primary bronchial epithelial cells (pBECs) and mouse model using several allergens including ovalbumin (OVA), house dust mite (HDM), or Alternaria alternata. We found that toll‐like receptor 2 (TLR2) was highly induced in ECs but not dendritic cells (DCs) by various allergens, leading to recruitment of circulating basophils into the lung via C‐C chemokine ligand‐2 (CCL2). TLR2 expression increased thymic stromal lymphopoietin (TSLP) production through the NF‐κB and JNK signaling pathways to extend the survival of recruited basophils and resident DCs in the lung, predisposing a type‐2‐cell‐mediated airway inflammation. Conversely, TLR2 deficiency impaired secretion of TSLP and CCL2, decreased infiltration of lung basophils, and increased resistance to Th2 response. Blocking TSLP also phenocopied these phenomena. Our findings reveal a pro‐inflammatory role of airway ECs through a TLR2‐dependent TSLP production, which may have implication for treating allergic asthma.

The DNA repair enzyme 8-oxoguanine DNA glycosylase 1 (OGG1), which excises 8-oxo-7,8-dihydroguanine lesions induced in DNA by reactive oxygen species, has been linked to the pathogenesis of lung diseases associated with bacterial infections. A recently developed small molecule, SU0268, has demonstrated selective inhibition of OGG1 activity; however, its role in attenuating inflammatory responses has not been tested. In this study, we report that SU0268 has a favorable effect on bacterial infection both in mouse alveolar macrophages (MH-S cells) and in C57BL/6 wild-type mice by suppressing inflammatory responses, particularly promoting type I IFN responses. SU0268 inhibited proinflammatory responses during Pseudomonas aeruginosa (PA14) infection, which is mediated by the KRAS–ERK1–NF-κB signaling pathway. Furthermore, SU0268 induces the release of type I IFN by the mitochondrial DNA–cGAS–STING–IRF3–IFN-β axis, which decreases bacterial loads and halts disease progression. Collectively, our results demonstrate that the small-molecule inhibitor of OGG1 (SU0268) can attenuate excessive inflammation and improve mouse survival rates during PA14 infection. This strong anti-inflammatory feature may render the inhibitor as an alternative treatment for controlling severe inflammatory responses to bacterial infection.