Stat6-deficient mice develop airway hyperresponsiveness and peribronchial fibrosis during chronic fungal asthma.
Signal transducer and activator of transcription 6 (Stat6) is critical for Th2-mediated responses during allergic airway disease. To investigate the role of Stat6 in fungus-induced airway hyperresponsiveness and remodeling, Stat6-deficient (Stat6-/-) and Stat6-wildtype (Stat6+/+) mice were sensitized to Aspergillus fumigatus and airway disease was subsequently assessed in both groups at days 21, 30, 38, and 44 after an intratracheal challenge with live A. fumigatus conidia. At all times after conidia, histological analysis revealed an absence of goblet cell hyperplasia and markedly diminished peribronchial inflammation in Stat6-/- mice in contrast to Stat6+/+ mice. Airway hyperresponsiveness and peribronchial fibrosis in Stat6-/- mice were significantly reduced at day 21 after conidia compared with Stat6+/+ mice, but both groups exhibited significant, similar increases in these parameters at all subsequent times after conidia. In separate experiments, IL-13-responsive cells in Stat6-/- mice were targeted via the daily intranasal administration of 200 ng of IL-13-PE38QQR (IL13-PE), comprised of human IL-13 and a derivative of Pseudomonas exotoxin, from days 38 to 44 after the conidia challenge. IL13-PE treatment abolished airway hyperresponsiveness, but not peribronchial fibrosis in Stat6-/- mice. Taken together, these data demonstrate that the chronic development of airway hyperresponsiveness during fungal asthma is IL-13-dependent but Stat6-independent.
Blease
Kate
K
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109-0602, USA.
Schuh
Jane M
JM
Jakubzick
Claudia
C
Lukacs
Nicholas W
NW
Kunkel
Steven L
SL
Joshi
Bharat H
BH
Puri
Raj K
RK
Kaplan
Mark H
MH
Hogaboam
Cory M
CM
D000818:Animals; D001229:Aspergillosis, Allergic Bronchopulmonary / Q000276:immunology / Q000503:physiopathology*; D001232:Aspergillus fumigatus; D001249:Asthma / Q000276:immunology / Q000382:microbiology / Q000503:physiopathology*; D016535:Bronchial Hyperreactivity / Q000276:immunology / Q000503:physiopathology*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D054413:Chemokine CCL11; D018932:Chemokine CCL2 / Q000378:metabolism; D018946:Chemokine CCL5 / Q000378:metabolism; D019742:Chemokines, CC / Q000378:metabolism; D002908:Chronic Disease; D003094:Collagen / Q000378:metabolism; D006801:Humans; D007073:Immunoglobulin E / Q000276:immunology / Q000378:metabolism; D018793:Interleukin-13 / Q000378:metabolism*; D015847:Interleukin-4 / Q000378:metabolism; D007962:Leukocytes / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000503:physiopathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D011658:Pulmonary Fibrosis / Q000276:immunology / Q000503:physiopathology*; D050800:STAT6 Transcription Factor; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000378:metabolism
C515456:CCL11 protein, human; C515457:Ccl11 protein, mouse; D054413:Chemokine CCL11; D018932:Chemokine CCL2; D018946:Chemokine CCL5; D019742:Chemokines, CC; D018793:Interleukin-13; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D015847:Interleukin-4; D007073:Immunoglobulin E; D003094:Collagen