Annexin A1 is a cell-intrinsic metalloregulator of zinc in human ILC2s.

Group 2 innate lymphoid cells (ILC2s) produce large amounts of type 2 cytokines including interleukin-5 (IL-5) and IL-13 in response to various stimuli, causing allergic and eosinophilic diseases. However, the cell-intrinsic regulatory mechanisms of human ILC2s remain unclear. Here, we analyze human ILC2s derived from different tissues and pathological conditions and identify ANXA1, encoding annexin A1, as a commonly highly expressed gene in non-activated ILC2s. The expression of ANXA1 decreases when ILC2s activate, but it increases autonomously as the activation subsides. Lentiviral vector-based gene transfer experiments show that ANXA1 suppresses the activation of human ILC2s. Mechanistically, ANXA1 regulates the expression of the metallothionein family genes, including MT2A, which modulate intracellular zinc homeostasis. Furthermore, increased intracellular zinc levels play an essential role in the activation of human ILC2s by promoting the mitogen-activated protein kinase (MAPK) and nuclear factor κB (NF-κB) pathways and GATA3 expression. Thus, the ANXA1/MT2A/zinc pathway is identified as a cell-intrinsic metalloregulatory mechanism for human ILC2s.

Anterior ethmoid and frontal sinus drainage pathways: five patterns formed and defined by their bony walls.

PURPOSE: To perform endoscopic sinus surgery safely and effectively, surgeons need to visualize the complex anatomy of the anterior ethmoid and frontal sinus region. Because this anatomy is so variable and individualized, the foundation of understanding lies in identifying, following, and visualizing the drainage pathway patterns and anticipating possible variations. METHODS: We studied 100 sides (50 cases: 22 male, 28 female, aged 12-86, average age 46.5 years, ± 19.5) using computed tomography (CT) and multiplanar reconstruction (MPR) to identify and classify the drainage pathways leading to the frontal sinus and anterior ethmoidal cells. RESULTS: Analysis revealed five patterns of drainage pathways defined by their bony walls: between the uncinate process and the lamina papyracea [UP-LP]; between the uncinate process and the middle turbinate [UP-MT]; between the uncinate process and the accessory uncinate process [UP-UPa]; between the uncinate process and the basal lamella of the ethmoidal bulla [UP-BLEB]; and between the basal lamella of the ethmoidal bulla and the basal lamella of the middle turbinate [BLEB-BLMT]. In most cases, BLEB formed the posterior wall of the drainage pathway of the frontal sinus, indicating BLEB could be one of the most important landmarks for approaching the frontal sinus. CONCLUSIONS: As endoscopic sinus surgery depends on an understanding of this anatomy, this study may help surgeons to identify and follow the drainage pathways more accurately and safely through the anterior ethmoid to the frontal sinus.

Dysregulated fatty acid metabolism in nasal polyp-derived eosinophils from patients with chronic rhinosinusitis.

BACKGROUND: Eosinophils are multifunctional granulocytes capable of releasing various cytokines, chemokines, and lipid mediators. We previously reported dysregulated fatty acid metabolism in peripheral blood-derived eosinophils from patients with severe asthma. However, functional characteristics of eosinophils present in allergic inflammatory tissues remain largely uncharacterized. METHODS: We established a method for isolating CD69hi CCR3low CXCR4- siglec-8int eosinophils from nasal polyps of patients with eosinophilic rhinosinusitis (NP-EOS). Multi-omics analysis including lipidomics, proteomics, and transcriptomics was performed to analyze NP-EOS as compared to peripheral blood-derived eosinophils from healthy subjects (PB-EOS). RESULTS: Lipidomic analysis revealed impaired synthesis of prostaglandins and 15-lipoxygenase (15-LOX)-derived mediators, and selective upregulation of leukotriene D4 production. Furthermore, proteomics and transcriptomics revealed changes in the expression of specific enzymes (GGT5, DPEP2, and 15-LOX) responsible for dysregulated lipid metabolism. Ingenuity pathway analysis indicated the importance of type 2 cytokines and pattern recognition receptor pathways. Stimulation of PB-EOS with eosinophil activators IL-5, GM-CSF, and agonists of TLR2 and NOD2 mimicked the observed changes in lipid metabolism. CONCLUSION: Inflammatory tissue-derived eosinophils possess a specific phenotype with dysregulated fatty acid metabolism that may be targeted therapeutically to control eosinophilic inflammatory diseases.