MTOR regulates metabolic adaptation of APCs in the lung microenvironment and controls the outcome of allergic inflammation
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus Musculus
TISSUE(S): Sorted Cells
DISEASE(S): Inflammation
PROVIDER: ST000657 | MetabolomicsWorkbench |
REPOSITORIES: MetabolomicsWorkbench
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Project description: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.
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Project description:BackgroundCD300a is an inhibitory receptor (IR) expressed on several leukocytes, including mast cells (MCs) and macrophages (MΦ), important cells in allergic inflammation (AI). We have previously characterized CD300a role on MCs and in vivo in mouse models of allergy, in which the absence of CD300a resulted in increased inflammatory features and delayed resolution. However, the exact mechanism of this delayed resolution is unclear. Our hypothesis is that MΦ, important players in resolution, might be impaired when CD300a is absent.ObjectivesThe aim of the study was to investigate CD300a-dependent functionality of mouse MΦ.MethodMΦ were purified from the peritoneum of wild-type (WT) and CD300a-/- mice naïve and 48 h and 96 h after challenge with ovalbumin/alum. Phenotype switching was analyzed via specific M1-M2 inducers and markers. MΦ phagocytotic ability was assessed via Staphylococcus aureus pHrodo-conjugated bioparticles. The influence of MCs on MΦ was investigated by incubating WT MΦ with supernatants from non-activated and IgE-activated bone marrow-derived MCs (BMMCs) and analyzing functional responses.ResultsNaïve CD300a-/- MΦ presented with increased sensitivity to activation when treated with LPS. Absence of CD300a results in increased Arg1 expression and increased IL-6 release when MΦ are purified from allergic peritonitis-induced mice. Similar results were obtained when CD300a-/- MΦ were purified 96 h after challenge. On the other hand, CD300a absence did not affect phagocytosis. WT MΦ incubated with supernatants of non-activated and IgE-activated BMMCs presented with increased iNOS expression and decreased Arg1 levels.ConclusionsThe IR CD300a controls the activation state of MΦ, and its absence could augment the inflammatory state seen in CD300a-/- mice. Moreover, MCs can also influence MΦ phenotype switching. This may partially explain the delayed AI resolution seen in these mice.
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