Role of lymphotoxin-alpha in cigarette smoke-induced inflammation and lymphoid neogenesis.
In chronic obstructive pulmonary disease (COPD), chronic inflammation is accompanied by peribronchial lymphoid aggregates. Lymphotoxin (LT)-alpha, 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 LTalpha knockout (LTalpha(-/-)) and wild-type (WT) mice and studied the 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 LTalpha(-/-) mice than in WT animals, and increased upon chronic CS exposure in both genotypes. In contrast, local immunoglobulin A responses upon chronic CS exposure were attenuated in LTalpha(-/-) mice. CXC chemokine ligand (CXCL) 13 and CC chemokine ligand (CCL) 19 mRNA in total lung and CXCL13 protein level in BALF increased upon CS exposure in WT, but not in LTalpha(-/-) mice. In vitro lymphotoxin-beta receptor (LTbetaR) stimulation induced CXCL13 and CCL19 mRNA in WT lung fibroblasts. Furthermore, in vitro exposure to CS extract upregulated CXCL13 mRNA expression in WT, but not in LTbetaR(-/-), lung fibroblasts. In this murine model of COPD, CS induces pulmonary expression of lymphoid chemokines CXCL13 and CCL19 in a LTalphabeta-LTbetaR-dependent fashion. However, LTalpha is not required for CS-induced pulmonary lymphocyte accumulation and neogenesis of lymphoid aggregates.
Demoor
T
T
Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium.
Bracke
K R
KR
Maes
T
T
Vandooren
B
B
Elewaut
D
D
Pilette
C
C
Joos
G F
GF
Brusselle
G G
GG
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D054415:Chemokine CCL19 / Q000096:biosynthesis; D054382:Chemokine CXCL13 / Q000096:biosynthesis; D005347:Fibroblasts / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced*; D008168:Lung / Q000166:cytology / Q000187:drug effects; D008221:Lymphoid Tissue / Q000187:drug effects / Q000378:metabolism; D053259:Lymphotoxin beta Receptor / Q000378:metabolism; D008233:Lymphotoxin-alpha / Q000378:metabolism*; D053308:Lymphotoxin-beta / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D029424:Pulmonary Disease, Chronic Obstructive / Q000503:physiopathology; D012906:Smoke; D012907:Smoking / Q000009:adverse effects*
C515461:Ccl19 protein, mouse; D054415:Chemokine CCL19; D054382:Chemokine CXCL13; C486386:Cxcl13 protein, mouse; D053259:Lymphotoxin beta Receptor; D008233:Lymphotoxin-alpha; D053308:Lymphotoxin-beta; D012906:Smoke