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

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.

Inhibition of B cell–dependent lymphoid follicle formation prevents lymphocytic bronchiolitis after lung transplantation

“…Grafts containing germinal centers, however, have a lower life expectancy, indicating a detrimental role for organized lymphoid follicles (73). Based on this knowledge, we targeted the GPCR EBI2, known to be specifically involved in the organization of B cells inside lymphoid follicles (26,31,74). Importantly, we show that EBI2 is expressed in tertiary lymphoid follicles in human BOS/CLAD.…”

Lymphatic impairment leads to pulmonary tertiary lymphoid organ formation and alveolar damage

“…Constitutive loss of CLEC2 results in an emphysematous lung phenotype. TLO formation is commonly seen in chronic lung inflammation and is associated with diverse lung diseases in humans (10,36), but whether TLO formation is connected to impaired lymphatic flow, and whether TLOs are a cause or a consequence of lung disease, remains unclear (50,51). The primary formation of TLOs in mice with impaired lymphatic flow led us to ask whether lymphatic impairment might result in lung injury and pathology.…”

Friend or Foe: The Protective and Pathological Roles of Inducible Bronchus-Associated Lymphoid Tissue in Pulmonary Diseases

“…SERPINE2 deficiency was associated with enhanced production of molecules associated with iBALT induction and inflammation, including IL-17, TNF-a, LTa, CXCL13, IFN-g, IL-2, and spontaneous mononuclear cell infiltration, thus boosting formation of iBALT in the lungs (76). Furthermore, using a mouse model of COPD, Jia et al (77) reported that oxysterol metabolism of cholesterol drove iBALT formation and the induction of COPD, similar to what occurs in SLOs. Increased production of a cholesterol-derived metabolite, 7a,25-hydroxy cholesterol, enhanced B cell recruitment into iBALT by interacting with EBV-induced G protein-coupled receptor 2 (EBI2), a G protein-coupled receptor also expressed in lymphocytes and DCs.…”