Abstract
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, and granulocyte-macrophage colony-stimulating factor) 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.
Highlights
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
Our findings indicate that Heme oxygenase-1 (HO-1) and its products are essential for primary airway epithelial cells (pAECs) survival to maintain airway epithelium homeostasis during NOD-like receptor protein 3 (NLRP3)–retinoid X receptor (RXR)– mediated apoptosis and inflammation
We explored whether RXR␣//␥ is involved in NLRP3induced apoptosis in airway epithelial cells and found that the expression of RXR␣//␥ was significantly reduced in pAECs treated with MCC950 (Fig. 2C)
Summary
Using primary airway epithelial cells (pAECs) and an asthma mouse model, we demonstrate that severe lung inflammation is associated with rapid pAEC apoptosis. Airway epithelial inflammation occurs in part in response to NACHT domain–, leucine-rich repeat–, and PYD-containing protein 3 (NLRP3) activation as well as the pro-inflammatory milieu in the lung [10]. NLRP3 contributes to target-organ damage in type 2 diabetes and cardiovascular and renal diseases [16, 17] It is unknown whether NLRP3 modulates airway epithelial cell apoptosis to control allergic lung inflammation. We demonstrated that activation of NLRP3–RXR␣//␥ axis promotes airway epithelial apoptosis and aggravates type 2 immune responses, whereas HO-1 efficiently inhibits this pathway and subsequent events in OVAinduced murine model of asthma
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