Fstl1 Promotes Asthmatic Airway Remodeling by Inducing Oncostatin M.
Chronic asthma is associated with airway remodeling and decline in lung function. In this article, we show that follistatin-like 1 (Fstl1), a mediator not previously associated with asthma, is highly expressed by macrophages in the lungs of humans with severe asthma. Chronic allergen-challenged Lys-Cre(tg) /Fstl1(Δ/Δ) mice in whom Fstl1 is inactivated in macrophages/myeloid cells had significantly reduced airway remodeling and reduced levels of oncostatin M (OSM), a cytokine previously not known to be regulated by Fstl1. The importance of the Fstl1 induction of OSM to airway remodeling was demonstrated in murine studies in which administration of Fstl1 induced airway remodeling and increased OSM, whereas administration of an anti-OSM Ab blocked the effect of Fstl1 on inducing airway remodeling, eosinophilic airway inflammation, and airway hyperresponsiveness, all cardinal features of asthma. Overall, these studies demonstrate that the Fstl1/OSM pathway may be a novel pathway to inhibit airway remodeling in severe human asthma.
Department of Medicine, University of California, San Diego, La Jolla, CA 92093;
Marina
M
Miller
Department of Medicine, University of California, San Diego, La Jolla, CA 92093;
Andrew
A
Beppu
Department of Medicine, University of California, San Diego, La Jolla, CA 92093;
Peter
P
Rosenthal
Department of Medicine, University of California, San Diego, La Jolla, CA 92093;
Alexa
A
Pham
Department of Medicine, University of California, San Diego, La Jolla, CA 92093;
Sudipta
S
Das
Department of Medicine, University of California, San Diego, La Jolla, CA 92093;
Maya
M
Karta
Department of Pediatrics, Korea University College of Medicine, Seoul 02841, Korea;
Dae Jin
DJ
Song
Department of Medicine, University of California, San Diego, La Jolla, CA 92093;
Christine
C
Vuong
Department of Medicine, University of California, San Diego, La Jolla, CA 92093;
Taylor
T
Doherty
Division of Immune Regulation, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037;
Michael
M
Croft
Department of Medicine, University of California, San Diego, La Jolla, CA 92093;
Bruce
B
Zuraw
Institute of Neuroscience, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China;
Xu
X
Zhang
Model Animal Research Center, Nanjing University, Nanjing 210061, China;
Xiang
X
Gao
Department of Medicine, University of California, San Diego, La Jolla, CA 92093; Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093; and.
Seema
S
Aceves
Meakins-Christie Laboratories of McGill University and McGill University Health Center Research Institute, Montreal, Quebec H2X 2p2, Canada.
Fazila
F
Chouiali
Meakins-Christie Laboratories of McGill University and McGill University Health Center Research Institute, Montreal, Quebec H2X 2p2, Canada.
Qutayba
Q
Hamid
Department of Medicine, University of California, San Diego, La Jolla, CA 92093; dbroide@ucsd.edu.
David H
DH
Broide
D056151:Airway Remodeling / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D001249:Asthma / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D005260:Female; D038702:Follistatin-Related Proteins / Q000235:genetics / Q000276:immunology*; D006801:Humans; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D053683:Oncostatin M / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology*
D000906:Antibodies; D038702:Follistatin-Related Proteins; C448720:Fstl1 protein, mouse; D053683:Oncostatin M; C448799:FSTL1 protein, human