TNF receptor-associated factor 1 expressed in resident lung cells is required for the development of allergic lung inflammation.
TNF is a major therapeutic target in a range of chronic inflammatory disorders, including asthma. TNFR-associated factor (TRAF)1 is an intracellular adaptor molecule important for signaling by TNFR. In this study, we investigated the role of TRAF1 in an adoptive transfer model of allergic lung inflammation. Mice deficient in TRAF1 (TRAF1(-/-)) and wild-type (WT) control animals were adoptively transferred with WT OVA-immune CD4(+) T cells, exposed to an aerosol of LPS-free OVA, and analyzed for the development of allergic lung inflammation. In contrast to WT mice, TRAF1(-/-) recipients failed to display goblet cell hyperplasia, eosinophilic inflammation, and airway hyperresponsiveness in this model of asthma. Neither T cell recruitment nor expression of the proinflammatory cytokines IL-4, IL-5, IL-13, or TNF occurred in the lungs of TRAF1(-/-) mice. Although purified myeloid TRAF1(-/-) dendritic cells (DCs) exhibited normal Ag-presenting function and transmigratory capacity in vitro and were able to induce OVA-specific immune responses in the lung draining lymph nodes (LNs) following adoptive transfer in vivo, CD11c(+)CD11b(+) DCs from airways of TRAF1(-/-) recipients were not activated, and purified draining LN cells did not proliferate in vitro. Moreover, transfer of WT or TRAF1(-/-) DCs failed to restore T cell recruitment and DC activation in the airways of TRAF1(-/-) mice, suggesting that the expression of TRAF1 in resident lung cells is required for the development of asthma. Finally, we demonstrate that T cell-transfused TRAF1(-/-) recipient mice demonstrated impaired up-regulation of ICAM-1 expression on lung cells in response to OVA exposure.
Oyoshi
Michiko K
MK
CBR Institute for Biomedical Research, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Bryce
Paul
P
Goya
Sho
S
Pichavant
Muriel
M
Umetsu
Dale T
DT
Oettgen
Hans C
HC
Tsitsikov
Erdyni N
EN
D019264:Adoptive Transfer; D000485:Allergens / Q000276:immunology; D000818:Animals; D017951:Antigen Presentation / Q000235:genetics; D001249:Asthma / Q000276:immunology* / Q000473:pathology; D039481:CD11b Antigen / Q000032:analysis; D039521:CD11c Antigen / Q000032:analysis; D003713:Dendritic Cells / Q000276:immunology / Q000637:transplantation; D004195:Disease Models, Animal; D001239:Inhalation; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D008168:Lung / Q000276:immunology* / Q000473:pathology; D008198:Lymph Nodes / Q000276:immunology; D051379:Mice; D008817:Mice, Mutant Strains; D010047:Ovalbumin / Q000276:immunology; D011014:Pneumonia / Q000276:immunology / Q000473:pathology; D012130:Respiratory Hypersensitivity / Q000276:immunology* / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology; D047990:TNF Receptor-Associated Factor 1 / Q000235:genetics / Q000502:physiology*
D000485:Allergens; D039481:CD11b Antigen; D039521:CD11c Antigen; D008070:Lipopolysaccharides; D047990:TNF Receptor-Associated Factor 1; D018799:Intercellular Adhesion Molecule-1; D010047:Ovalbumin