Toll-like receptor 9 activation is a key mechanism for the maintenance of chronic lung inflammation.
BACKGROUND
Accumulating evidence supports the hypothesis that the continuous host response to a persistent challenge can polarize the cytokine environment toward a Th2 cytokine phenotype, but the mechanisms responsible for this skewing are not clear.


OBJECTIVE
We investigated the role of Toll-like receptor 9 (TLR9) in a Th2-driven pulmonary granulomatous response initiated via the embolization of Schistosoma mansoni eggs to the lungs of mice.


METHODS
Mice were intravenously injected with S. mansoni eggs. Histological and flow cytometric analysis, cytokine measurement, adoptive transfer of bone marrow (BM)-derived dendritic cells (DCs), and in vitro T-cell treatments with antigen-presenting cells were examined.


RESULTS
In comparison to wild-type mice, TLR9(-/-) mice showed increased pulmonary granuloma size, augmented collagen deposition, increased Th2 cytokine phenotype, and impaired accumulation of DCs. BM-derived DCs, but not macrophages, recovered from animals with developed Th2-type lung granulomas promoted the production of type 2 cytokines from CD4(+) T cells. BM-derived DCs from TLR9(-/-) mice induced impaired Th1 cytokine and enhanced Th2 cytokine production by T cells, compared with DCs from WT mice. Macrophages from TLR9(-/-) mice expressed a significantly higher alternatively activated (M2) phenotype characterized by increased "found in inflammatory zone-1" (FIZZ1) and arginase-1 expression. The adoptive transfer of BM-derived DCs from syngeneic WT mice into TLR9(-/-) mice restored the granuloma phenotype seen in WT mice.


CONCLUSIONS
These studies suggest that TLR9 plays an important mechanistic role in the maintenance of the pulmonary granulomatous response.
Ito
Toshihiro
T
Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
Schaller
Matthew
M
Raymond
Tracy
T
Joshi
Amrita D
AD
Coelho
Ana L
AL
Frantz
Fabiani G
FG
Carson
William F
WF
Hogaboam
Cory M
CM
Lukacs
Nicholas W
NW
Standiford
Theodore J
TJ
Phan
Sem H
SH
Chensue
Stephen W
SW
Kunkel
Steven L
SL
D000818:Animals; D002908:Chronic Disease; D003713:Dendritic Cells / Q000276:immunology; D004195:Disease Models, Animal; D005434:Flow Cytometry; D015769:Granuloma, Respiratory Tract / Q000150:complications / Q000276:immunology*; D007249:Inflammation / Q000150:complications / Q000276:immunology*; D008168:Lung; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012550:Schistosoma mansoni / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000276:immunology*
D051217:Toll-Like Receptor 9