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Role of CXCL13 in cigarette smoke-induced lymphoid follicle formation and chronic obstructive pulmonary disease

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Ghent researchers on unfolded proteins in inflammatory disease (GROUP-ID)
Abstract
Rationale: The B cell-attracting chemokine CXCL13 is an important mediator in the formation of tertiary lymphoid organs (TLOs). Increased numbers of ectopic lymphoid follicles have been observed in lungs of patients with severe chronic obstructive pulmonary disease (COPD). However, the role of these TLOs in the pathogenesis of COPD remains unknown. Objectives: By neutralizing CXCL13 in a mouse model of chronic cigarette smoke (CS) exposure, we aimed at interrogating the link between lymphoid follicles and development of pulmonary inflammation, emphysema, and airway wall remodeling. Methods: We first quantified and localized CXCL13 in lungs of air-or CS-exposed mice and in lungs of never smokers, smokers without airflow obstruction, and patients with COPD by reverse transcriptase-polymerase chain reaction, ELISA, and immunohistochemistry. Next, CXCL13 signaling was blocked by prophylactic or therapeutic administration of anti-CXCL13 antibodies in mice exposed to air or CS for 24 weeks, and several hallmarks of COPD were evaluated. Measurements and Main Results: Both mRNA and protein levels of CXCL13 were increased in lungs of CS-exposed mice and patients with COPD. Importantly, expression of CXCL13 was observed within B-cell areas of lymphoid follicles. Prophylactic and therapeutic administration of anti-CXCL13 antibodies completely prevented the CS-induced formation of pulmonary lymphoid follicles in mice. Interestingly, absence of TLOs attenuated destruction of alveolar walls and inflammation in bronchoalveolar lavage but did not affect airway wall remodeling. Conclusions: CXCL13 is produced within lymphoid follicles of patients with COPD and is crucial for the formation of TLOs. Neutralization of CXCL13 partially protects mice against CS-induced inflammation in bronchoalveolar lavage and alveolar wall destruction.
Keywords
lymphoid follicles, CXCL13, DENDRITIC CELLS, B-CELL, INDUCED EMPHYSEMA, MURINE MODEL, PLASMA-CELLS, MICE, COPD, INFLAMMATION, NEOGENESIS, EXPRESSION, chronic obstructive pulmonary disease, cigarette smoke

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Citation

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Chicago
Bracke, Ken, Fien Verhamme, Leen Seys, Claudie Bantsimba-Malanda, Danen Mootoosamy Cunoosamy, Ronald Herbst, Hamida Hammad, Bart Lambrecht, Guy Joos, and Guy Brusselle. 2013. “Role of CXCL13 in Cigarette Smoke-induced Lymphoid Follicle Formation and Chronic Obstructive Pulmonary Disease.” American Journal of Respiratory and Critical Care Medicine 188 (3): 343–355.
APA
Bracke, Ken, Verhamme, F., Seys, L., Bantsimba-Malanda, C., Mootoosamy Cunoosamy, D., Herbst, R., Hammad, H., et al. (2013). Role of CXCL13 in cigarette smoke-induced lymphoid follicle formation and chronic obstructive pulmonary disease. AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 188(3), 343–355.
Vancouver
1.
Bracke K, Verhamme F, Seys L, Bantsimba-Malanda C, Mootoosamy Cunoosamy D, Herbst R, et al. Role of CXCL13 in cigarette smoke-induced lymphoid follicle formation and chronic obstructive pulmonary disease. AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE. 2013;188(3):343–55.
MLA
Bracke, Ken, Fien Verhamme, Leen Seys, et al. “Role of CXCL13 in Cigarette Smoke-induced Lymphoid Follicle Formation and Chronic Obstructive Pulmonary Disease.” AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE 188.3 (2013): 343–355. Print.
@article{4145358,
  abstract     = {Rationale: The B cell-attracting chemokine CXCL13 is an important mediator in the formation of tertiary lymphoid organs (TLOs). Increased numbers of ectopic lymphoid follicles have been observed in lungs of patients with severe chronic obstructive pulmonary disease (COPD). However, the role of these TLOs in the pathogenesis of COPD remains unknown.
Objectives: By neutralizing CXCL13 in a mouse model of chronic cigarette smoke (CS) exposure, we aimed at interrogating the link between lymphoid follicles and development of pulmonary inflammation, emphysema, and airway wall remodeling.
Methods: We first quantified and localized CXCL13 in lungs of air-or CS-exposed mice and in lungs of never smokers, smokers without airflow obstruction, and patients with COPD by reverse transcriptase-polymerase chain reaction, ELISA, and immunohistochemistry. Next, CXCL13 signaling was blocked by prophylactic or therapeutic administration of anti-CXCL13 antibodies in mice exposed to air or CS for 24 weeks, and several hallmarks of COPD were evaluated.
Measurements and Main Results: Both mRNA and protein levels of CXCL13 were increased in lungs of CS-exposed mice and patients with COPD. Importantly, expression of CXCL13 was observed within B-cell areas of lymphoid follicles. Prophylactic and therapeutic administration of anti-CXCL13 antibodies completely prevented the CS-induced formation of pulmonary lymphoid follicles in mice. Interestingly, absence of TLOs attenuated destruction of alveolar walls and inflammation in bronchoalveolar lavage but did not affect airway wall remodeling.
Conclusions: CXCL13 is produced within lymphoid follicles of patients with COPD and is crucial for the formation of TLOs. Neutralization of CXCL13 partially protects mice against CS-induced inflammation in bronchoalveolar lavage and alveolar wall destruction.},
  author       = {Bracke, Ken and Verhamme, Fien and Seys, Leen and Bantsimba-Malanda, Claudie and Mootoosamy Cunoosamy, Danen and Herbst, Ronald and Hammad, Hamida and Lambrecht, Bart and Joos, Guy and Brusselle, Guy},
  issn         = {1073-449X},
  journal      = {AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE},
  keyword      = {lymphoid follicles,CXCL13,DENDRITIC CELLS,B-CELL,INDUCED EMPHYSEMA,MURINE MODEL,PLASMA-CELLS,MICE,COPD,INFLAMMATION,NEOGENESIS,EXPRESSION,chronic obstructive pulmonary disease,cigarette smoke},
  language     = {eng},
  number       = {3},
  pages        = {343--355},
  title        = {Role of CXCL13 in cigarette smoke-induced lymphoid follicle formation and chronic obstructive pulmonary disease},
  url          = {http://dx.doi.org/10.1164/rccm.201211-2055OC},
  volume       = {188},
  year         = {2013},
}

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