Role of Lymphotoxin- in Cigarette Smoke-Induced Inflammation and Lymphoid Neogenesis

¹ Dept of Respiratory Medicine, Laboratory for Translational Research in Obstructive Pulmonary Diseases, Ghent University Hospital, Ghent, Belgium
² Dept of Rheumatology, Laboratory of Molecular Immunology and Inflammation, Ghent University Hospital, Ghent, Belgium
³ Unit of Pneumology and Microbiology, Dept of Pneumology, Cliniques Universitaires St-Luc, Université Catholique de Louvain (UCL), Brussels, Belgium

^* To whom correspondence should be addressed. E-mail: guy.brusselle{at}ugent.be.

	Abstract

In chronic obstructive pulmonary disease (COPD), chronic inflammation is accompanied by peribronchial lymphoid aggregates. Lymphotoxin- (LT), crucial in secondary lymphoid organogenesis, may be involved in lymphoid neogenesis.

We examined cigarette smoke (CS)-induced pulmonary lymphoid neogenesis and inflammation in vivo in LT knockout (LT^-/-) and wild-type (WT) mice and studied expression of lymphoid chemokines by lung fibroblasts in vitro.

T-cell numbers (in bronchoalveolar lavage fluid (BALF) and lungs) and lymphoid aggregate numbers were significantly higher in air-exposed LT^-/- mice than in WT animals, and increased upon chronic CS exposure in both genotypes. In contrast, local IgA responses upon chronic CS exposure were attenuated in LT^-/- mice. CXCL13 and CCL19 mRNA in total lung and CXCL13 protein level in BALF increased upon CS exposure in WT, but not in LT^-/- mice. In vitro lymphotoxin- receptor (LTR) stimulation induced CXCL13 and CCL19 mRNA in WT lung fibroblasts. Furthermore, in vitro exposure to cigarette smoke extract (CSE) up-regulated CXCL13 mRNA expression in WT, but not in LTR^-/-, lung fibroblasts.

In this murine model of COPD, CS induces pulmonary expression of lymphoid chemokines CXCL13 and CCL19 in a LT-LTR-dependent fashion. However, LT is not required for CS-induced pulmonary lymphocyte accumulation and neogenesis of lymphoid aggregates.

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