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. 2010 Jun 1;181(11):1250-61.
doi: 10.1164/rccm.200909-1337OC. Epub 2010 Mar 1.

Fas/Fas ligand-mediated apoptosis promotes hypersensitivity pneumonitis in mice by enhancing maturation of dendritic cells

Su Jin Hwang  1 , Hye Sung Kim, Doo Hyun Chung
Affiliations

Fas/Fas ligand-mediated apoptosis promotes hypersensitivity pneumonitis in mice by enhancing maturation of dendritic cells

Su Jin Hwang et al. Am J Respir Crit Care Med. .

Abstract

Rationale: 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.

Objectives: 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.

Measurements and main 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.

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