Fas/Fas ligand-mediated apoptosis promotes hypersensitivity pneumonitis in mice by enhancing maturation of dendritic cells.
BACKGROUND
Fas/Fas ligand (FasL)-mediated apoptosis has been implicated in various lung diseases, but whether Fas/FasL-mediated apoptosis in the lungs plays a critical role in the development of hypersensitivity pneumonitis (HP) is unclear.


OBJECTIVE
To explore the functional roles of Fas/FasL-mediated apoptosis in HP.


METHODS
Fas-deficient (lpr/lpr), FasL-deficient (gld/gld), and B6 mice were challenged with Saccharopolyspora rectivirgula (SR) antigen intranasally.


RESULTS
lpr/lpr and gld/gld mice exhibited attenuation of HP in terms of histological alterations, influx of immune cells in bronchoalveolar lavage fluid (BALF), and SR-specific immune responses compared with B6 mice, similar to the effects of SR in B6 mice given a caspase inhibitor. The lungs of lpr/lpr and gld/gld mice showed high IL-4 production and low IFN-gamma, IL-8, macrophage inflammatory protein-2, IL-1beta, and tumor necrosis factor-alpha production compared with those of B6 mice. Moreover, mice with chimeric B6 and lpr/lpr bone marrow revealed that apoptosis of nonhematopoietic and BALF immune cells of the lungs enhanced immune responses against SR antigen. Gr-1(+) granulocytes in BALF expressed annexin V and their depletion in B6 mice attenuated HP. Apoptosis of nonhematopoietic cells and Gr-1(+) granulocytes in the lungs enhanced the maturation of pulmonary CD11c(+) dendritic cells and their production of macrophage inflammatory protein-1alpha and monocyte chemoattractant protein-1, resulting in recruitment of immune cells into the lungs during HP.


CONCLUSIONS
These results suggest that apoptosis in nonhematopoietic cells and Gr-1(+) granulocytes of the lungs promotes HP by enhancing maturation and chemokine production of CD11c(+) dendritic cells.
Hwang
Su Jin
SJ
Department of Pathology and Laboratory of Immune Regulation, Department of Biosciences, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, Seoul 110-799, Korea.
Kim
Hye Sung
HS
Chung
Doo Hyun
DH
D000542:Alveolitis, Extrinsic Allergic / Q000473:pathology*; D000818:Animals; D017209:Apoptosis; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology*; D004847:Epithelial Cells / Q000378:metabolism; D053222:Fas Ligand Protein / Q000378:metabolism*; D005434:Flow Cytometry; D006098:Granulocytes / Q000378:metabolism; D007694:Killer Cells, Natural / Q000378:metabolism; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C
D016207:Cytokines; D053222:Fas Ligand Protein