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

Am J Respir Crit Care Med. 2013 Aug 1;188(3):343-55. doi: 10.1164/rccm.201211-2055OC.

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Airway Remodeling / drug effects
  • Animals
  • Bronchoalveolar Lavage Fluid / chemistry
  • Chemokine CXCL13 / biosynthesis
  • Chemokine CXCL13 / drug effects
  • Chemokine CXCL13 / genetics*
  • Disease Models, Animal
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Gene Expression Regulation*
  • Humans
  • Immunohistochemistry
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Middle Aged
  • Polymerase Chain Reaction
  • Pulmonary Disease, Chronic Obstructive / complications*
  • Pulmonary Disease, Chronic Obstructive / genetics
  • Pulmonary Disease, Chronic Obstructive / physiopathology
  • RNA, Messenger / genetics*
  • Smoke / adverse effects*
  • Smoking / adverse effects*
  • Smoking / genetics
  • Smoking / metabolism
  • Tobacco*

Substances

  • Chemokine CXCL13
  • Cxcl13 protein, mouse
  • RNA, Messenger
  • Smoke