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A1189 - Immuno-Metabolomic Regulation of B Cell Guided iBALT Positioning Drives Cigarette Smoke-Induced COPD
Author Block: T. M. Conlon1, R. S. Sarker1, J. Jia1, K. Heinzelmann1, D. Tasdemir2, H. Bayram3, O. Eickelberg4, A. Yildirim1; 1Comprehensive Pneumology Center, Institute of Lung Biology and Disease, Helmholtz Zentrum München, Member of the German Center for Lung Research (DZL), Munich, Germany, 2Department of Chest Diseases, School of Medicine, University of Gaziantep, Gaziantep, Turkey, 3Pulmonary Medicine, Koc University School of Medicine, Istanbul, Turkey, 4Pulmonary Sciences and Critical Care Medicine, Univ of Colorado Denver, Denver, CO, United States.
Chronic obstructive pulmonary disease (COPD) is a leading cause of chronic mortality and morbidity worldwide with limited therapeutic options. It is characterized by progressive and largely irreversible airflow limitation, resulting from long-term exposure to toxic gases and particles, in particular cigarette smoke (CS). CS exposure induces chronic bronchitis, small airway remodeling and emphysema. Network analysis recently revealed that emphysema development is strongly correlated with a prominent B cell signature (Faner et al. 2016). Furthermore, we have shown that an absence of B cells impaired inducible bronchus-associated lymphoid tissue (iBALT) formation, and prevented CS-induced emphysema in animal models of COPD (John-Schuster et al. 2014). The mechanism underlying iBALT positioning upon the bronchi, however, remains to be defined. The oxysterol metabolism of cholesterol, generating 7α,25-dihydroxycholesterol and acting through the G protein-coupled receptor EBI2 expressed on B cells has recently emerged as a central pathway that regulates the structure and function of secondary lymphoid tissue. Here, we demonstrate the importance of this pathway for the immune pathogenesis of COPD.
Wild-type and EBI2 deficient C57BL/6 mice were exposed to CS (500mg/m3 total particulate matter) for 50 mins twice a day for 4 months, while control animals received filtered air (FA). Flow cytometry was undertaken to assess immune cell recruitment to the lung, and stereological assessment of lung tissue sections using computer associated unbiased methodology (Visiopharm) to quantify iBALT generation and airspace enlargement. In addition, gene expression analysis (RNA-Seq and qRT-PCR) was undertaken on murine and COPD patient lung tissue.
Wild-type mice exposed to CS developed clear evidence of emphysema accompanied by iBALT formation, while EBI2 deficient animals failed to generate iBALT, and were protected against emphysema. Intriguingly, immune cell recruitment to the lungs and BALF was equivalent in both EBI2 deficient and wild-type mice, suggesting EBI2 is important for cellular positioning and not recruitment to the lung. In support, both COPD patients and CS-exposed mice strongly upregulated airway expression of CH25H and CYP7B1, oxysterol metabolizing enzymes critical for EBI2 ligand synthesis. Furthermore, mice deficient in CH25H, lacked oxysterol synthesis and were also protected from CS-induced emphysema and iBALT.
In conclusion, oxysterol metabolism and EBI2 guided B cell positioning is critical for iBALT formation and subsequent COPD pathogenesis, revealing a novel mechanism and highlighting alternative therapeutic targets for the treatment of COPD.