Fas-activated serine/threonine phosphoprotein promotes immune-mediated pulmonary inflammation.
We generated Fas-activated serine threonine phosphoprotein (FAST)-deficient mice (FAST(-/-)) to study the in vivo role of FAST in immune system function. In a model of house dust mite-induced allergic pulmonary inflammation, wild type mice develop a mixed cellular infiltrate composed of eosinophils, lymphocytes, and neutrophils. FAST(-/-) mice develop airway inflammation that is distinguished by the near absence of neutrophils. Similarly, LPS-induced alveolar neutrophil recruitment is markedly reduced in FAST(-/-) mice compared with wild type controls. This is accompanied by reduced concentrations of cytokines (TNF-alpha and IL-6 and -23) and chemoattractants (MIP-2 and keratinocyte chemoattractant) in bronchoalveolar lavage fluids. Because FAST(-/-) neutrophils exhibit normal chemotaxis and survival, impaired neutrophil recruitment is likely to be due to reduced production of chemoattractants within the pulmonary parenchyma. Studies using bone marrow chimeras implicate lung resident hematopoietic cells (e.g., pulmonary dendritic cells and/or alveolar macrophages) in this process. In conclusion, our results introduce FAST as a proinflammatory factor that modulates the function of lung resident hematopoietic cells to promote neutrophil recruitment and pulmonary inflammation.
Simarro
Maria
M
Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Smith 652, One Jimmy Fund Way, Boston, MA 02115, USA.
Giannattasio
Giorgio
G
De la Fuente
Miguel A
MA
Benarafa
Charaf
C
Subramanian
Kulandayan K
KK
Ishizawar
Rumey
R
Balestrieri
Barbara
B
Andersson
Emma M
EM
Luo
Hongbo R
HR
Orduña
Antonio
A
Boyce
Joshua
J
Anderson
Paul
P
D055371:Acute Lung Injury / Q000235:genetics / Q000276:immunology / Q000473:pathology; D000485:Allergens / Q000008:administration & dosage / Q000276:immunology; D000818:Animals; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000235:genetics / Q000276:immunology; D040002:Dermatophagoides pteronyssinus / Q000276:immunology; D004391:Dust / Q000276:immunology; D005260:Female; D006410:Hematopoiesis / Q000235:genetics / Q000276:immunology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D024101:Mitochondrial Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D020556:Neutrophil Infiltration / Q000235:genetics / Q000276:immunology; D010750:Phosphoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D016601:RNA-Binding Proteins / Q000502:physiology; D012130:Respiratory Hypersensitivity / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D000074019:T-Cell Intracellular Antigen-1; D019014:fas Receptor / Q000502:physiology*
D000485:Allergens; D004391:Dust; D024101:Mitochondrial Proteins; D010750:Phosphoproteins; D016601:RNA-Binding Proteins; D000074019:T-Cell Intracellular Antigen-1; C499367:Tia1 protein, mouse; D019014:fas Receptor; C550470:FAST protein, mouse; D017346:Protein Serine-Threonine Kinases