Phosphoinositide 3-kinase-δ regulates fungus-induced allergic lung inflammation through endoplasmic reticulum stress

Abstract

BackgroundSensitisation with Aspergillus fumigatus (Af) is known to be associated with severe allergic lung inflammation, but the mechanism remains to be clarified. Phosphoinositide 3-kinase (PI3K)-δ and endoplasmic reticulum (ER) stress are suggested to be involved in steroid-resistant lung inflammation. We aimed to elucidate the role of PI3K-δ and its relationship with ER stress in fungus-induced allergic lung inflammation.MethodsUsing Af-exposed in vivo and in vitro experimental systems, we examined whether PI3K-δ regulates ER stress, thereby contributing to steroid resistance in fungus-induced allergic lung inflammation. Moreover, we checked expression of an ER stress marker in lung tissues isolated from patients with allergic bronchopulmonary aspergillosis.ResultsAf-exposed mice showed that ER stress markers, unfolded protein response (UPR)-related proteins, phosphorylated Akt, generation of mitochondrial reactive oxygen species (mtROS), eosinophilic allergic inflammation, and airway hyperresponsiveness (AHR) were increased in the lung. Similarly, glucose-regulated protein 78 was increased in lung tissues of patients with ABPA. A PI3K-δ inhibitor reduced Af-induced increases in ER stress markers, UPR-related proteins, allergic inflammation and AHR in mice. However, dexamethasone failed to reduce Af-induced allergic inflammation, AHR and elevation of ER stress. Administration of an ER stress inhibitor or a mtROS scavenger improved Af-induced allergic inflammation. The PI3K-δ inhibitor reduced Af-induced mtROS generation and the mtROS scavenger ameliorated ER stress. In primary cultured tracheal epithelial cells, Af-induced ER stress was inhibited by blockade of PI3K-δ.ConclusionsThese findings suggest that PI3K-δ regulates Af-induced steroid-resistant eosinophilic allergic lung inflammation through ER stress.

Oxidative and endoplasmic reticulum stress in respiratory disease

“…Studies of ER stress in the human disease are rather limited but there is evidence of ER stress in both cells sampled by bronchiolar lavage and in peripheral blood leucocytes 90. A range of animal models of allergy and asthma have also implicated ER stress in the pathophysiology of these conditions 90, 91, 92, 93, 94, 95, 96. Airway goblet cell hyperplasia and mucus hypersecretion are characteristics of most forms of asthma and the increased biosynthetic load in these cells may be principal drivers of ER stress, as may the ROS/RNS released by phagocytes, particularly in neutrophilic disease.…”

Kinases as Novel Therapeutic Targets in Asthma and Chronic Obstructive Pulmonary Disease

“…In the murine model of asthma, intratracheal administration of IC87114 suppressed the allergic response, Th2 cytokines, and AHR (Lee et al, 2006a), and these effects are mirrored in PI3Kd-inactivated mice (Nashed et al, 2007). In an Aspergillus fumigatus model of allergic inflammation in mice, PI3Kd inhibition suppressed the allergic response, and this effect was mediated through inhibition of endoplasmic reticulum stress, which is increased in asthma and results in NF-kB activation (Lee et al, 2016). PI3K may also play a role in increasing contractility of canine airway smooth muscle (Halayko et al, 2004) and the increased proliferation of airway smooth muscle in response to growth factors such as TGF-b (Goldsmith et al, 2006).…”

Lyn kinase represses mucus hypersecretion by regulating IL-13-induced endoplasmic reticulum stress in asthma

“…Previous studies showed that PI3K-δ regulates Aspergillus fumigatus -induced allergic lung inflammation through ER stress (Lee et al, 2016). To investigate whether Lyn is involved in ER stress in the pathogenesis of bronchial asthma, we also measured the levels of ER stress markers and PI3K/Akt/NFκB in the lung tissue of WT mice and Lyn-TG mice exposed to OVA.…”

“…Aspergillus fumigatus is also associated with steroid-resistant eosinophilic allergic lung inflammation via ER stress. Phosphoinositide 3-kinase-δ (PI3K-δ) regulates fungus-induced allergic lung inflammation via endoplasmic reticulum stress (Lee et al, 2016). Furthermore, oxidative stress causes mucin synthesis via the transactivation of epidermal growth factor receptor (EGFR), but MUC5AC synthesis is not inhibited by antioxidants (Takeyama et al, 2000).…”