TLR3 modulates immunopathology during a Schistosoma mansoni egg-driven Th2 response in the lung.
We examined the role of TLR3 in Th2-driven pulmonary granulomatous disease, using wildtype (TLR3(+/+)) and TLR3 gene-deficient (TLR3(-/-)) mice in a well-established model of Schistosoma mansoni egg-induced pulmonary granuloma. The intravenous bolus injection of S. mansoni eggs into S. mansoni-sensitized TLR3(+/+) mice was associated with an increase in TLR3 transcript expression in alveolar macrophages and ex vivo spleen and lung cultures at day 8 after egg injection. Lungs from TLR3(-/-) mice showed an increase in granuloma size, greater collagen deposition around the granuloma, and increased Th2 cytokine and chemokine levels compared with similarly sensitized and challenged TLR3(+/+) mice. Macrophages from TLR3(-/-) mice exhibited an M2 phenotype characterized by increased arginase and CCL2 expression. Significantly greater numbers of CD4(+)CD25(+) T cells were present in the lungs of TLR3(-/-) mice compared with TLR3(+/+) mice at day 8 after egg embolization. Cells derived from granulomatous lung and lung draining lymph nodes of TLR3(-/-) mice released significantly higher levels of IL-17 levels relative to TLR3(+/+) cells. Thus, our data suggest that TLR3 has a major regulatory role during a Th2-driven granulomatous response as its absence enhanced immunopathology.
Joshi
Amrita D
AD
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109-0602, USA.
Schaller
Matthew A
MA
Lukacs
Nicholas W
NW
Kunkel
Steven L
SL
Hogaboam
Cory M
CM
D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D007113:Immunity, Innate / Q000276:immunology; D008171:Lung Diseases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010063:Ovum / Q000276:immunology*; D010641:Phenotype; D012550:Schistosoma mansoni / Q000276:immunology*; D012555:Schistosomiasis mansoni / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D013154:Spleen / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism; D051196:Toll-Like Receptor 3 / Q000172:deficiency / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics
D016207:Cytokines; C519703:TLR3 protein, mouse; D051196:Toll-Like Receptor 3