Cholesterol metabolism promotes B-cell positioning during immune pathogenesis of chronic obstructive pulmonary disease.

Jie Jia,Katharina Heinzelmann,Martin Irmler,Jerzy Adamski,Oliver Eickelberg,Barkha Srivastava,Demet Taşdemir,Gizem Güneş,Jiaqi Gao,Hasan Bayram,Ralf Zimmermann,Johannes Beckers,Michael Schloter,Xiao Wu,Jutta Lintelmann,Ali Önder Yildirim,Cornelia Prehn,Stefan Pfeiffer,Stijn E Verleden ,Natalia F Smirnova ,Thomas M Conlon ,Rim S.j Sarker ,Martin Hrabě De Angelis

doi:10.15252/emmm.201708349

Abstract

The development of chronic obstructive pulmonary disease (COPD) pathogenesis remains unclear, but emerging evidence supports a crucial role for inducible bronchus‐associated lymphoid tissue (iBALT) in disease progression. Mechanisms underlying iBALT generation, particularly during chronic CS exposure, remain to be defined. Oxysterol metabolism of cholesterol is crucial to immune cell localization in secondary lymphoid tissue. Here, we demonstrate that oxysterols also critically regulate iBALT generation and the immune pathogenesis of COPD. In both COPD patients and cigarette smoke (CS)‐exposed mice, we identified significantly upregulated CH25H and CYP7B1 expression in airway epithelial cells, regulating CS‐induced B‐cell migration and iBALT formation. Mice deficient in CH25H or the oxysterol receptor EBI2 exhibited decreased iBALT and subsequent CS‐induced emphysema. Further, inhibition of the oxysterol pathway using clotrimazole resolved iBALT formation and attenuated CS‐induced emphysema in vivo therapeutically. Collectively, our studies are the first to mechanistically interrogate oxysterol‐dependent iBALT formation in the pathogenesis of COPD, and identify a novel therapeutic target for the treatment of COPD and potentially other diseases driven by the generation of tertiary lymphoid organs.

Highlights

Chronic obstructive pulmonary disease (COPD) is a leading cause of chronic mortality and morbidity worldwide with limited therapeutic options, characterized by progressive and largely irreversible airflow limitation resulting from long-term exposure to toxic gases and particles, in particular cigarette smoke (CS; Berndt et al, 2012; Vogelmeier et al, 2017)
Oxysterol metabolism increases in airway epithelial cells of chronic obstructive pulmonary disease (COPD) patients and mouse Airway epithelial cells secrete a plethora of immune mediators (Benam et al, 2016), yet immunological factors that orchestrate inducible bronchus-associated lymphoid tissue (iBALT) positioning remain to be defined
This study reveals a role for oxysterol metabolism in guiding iBALT generation to the airways during COPD pathogenesis

Summary

Introduction

Chronic obstructive pulmonary disease (COPD) is a leading cause of chronic mortality and morbidity worldwide with limited therapeutic options, characterized by progressive and largely irreversible airflow limitation resulting from long-term exposure to toxic gases and particles, in particular cigarette smoke (CS; Berndt et al, 2012; Vogelmeier et al, 2017). This induces chronic bronchitis, small airway remodeling, and emphysema (loss of septal tissue; Tuder & Petrache, 2012). Their causative role against COPD development and the mechanism underlying iBALT positioning upon the bronchus, remains to be defined

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Conclusion