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IL11 (Interleukin-11) Causes Emphysematous Lung Disease in a Mouse Model of Marfan Syndrome
Benjamin Ng1,2, Chen Xie1, Liping Su1
1National Heart Research Institute Singapore, National Heart Centre Singapore (B.N., C.X., L.S., X.-Y.K., D.Y., C.J.P., S.A.C., W.-W.L.).
Background:
Marfan Syndrome (MFS) is an inherited connective tissue disorder caused by mutations in the FBN1 (fibrillin-1) gene. Lung abnormalities are common in MFS, but their pathogenesis is poorly understood. IL11 (interleukin-11) causes aortic disease in a mouse model of MFS and was studied here in the lung.
Methods:
We examined histological and molecular phenotypes in the lungs of Fbn1C1041G/+ mice (mouse model of Marfan Syndrome [mMFS]), an established mouse model of MFS. To identify IL11-expressing cells, we used immunohistochemistry on lungs of 4- and 16-week-old Fbn1C1041G/+:Il11EGFP/+ reporter mice. We studied the effects of IL11 inhibition by RT-qPCR, immunoblots and histopathology in lungs from genetic or pharmacologic models: (1) 16-week-old IL11 receptor (IL11RA) knockout mMFS mice (Fbn1C1041G/+:Il11ra1-/- mice) and (2) in mMFS mice administered IgG control or interleukin-11 receptor antibodies twice weekly from 4 to 24 weeks of age.
Results:
mMFS lungs showed progressive loss and enlargement of distal airspaces associated with increased proinflammatory and profibrotic gene expression as well as matrix metalloproteinases 2, 9, and 12. IL11 was increased in mMFS lungs and localized to smooth muscle and endothelial cells in young mMFS mice in the Fbn1C1041G/+:Il11EGFP/+ reporter strain and in fibroblasts, in older mice. In mMFS mice, genetic (Fbn1C1041G/+:Il11ra1-/-) or pharmacologic (anti-interleukin-11 receptor) inhibition of IL11 signaling reduced lung emphysema, fibrosis, and inflammation. This protective effect was associated with reduced pathogenic ERK1/2 signaling and lower metalloproteinase 2, 9, and 12 expression.
Conclusions:
IL11 causes lung disease in mMFS. This reveals a shared IL11-driven disease mechanism in lung and aorta in MFS and suggests inhibition of IL11 signaling as a holistic approach for treating multiorgan morbidity in MFS.
Insights
Interleukin-11 (IL11) drives lung disease in Marfan syndrome (MFS) models. Inhibiting IL11 signaling ameliorates emphysema, fibrosis, and inflammation, offering a potential treatment for MFS lung complications.
Area of Science:
- Genetics and Molecular Biology
- Pathology
- Medical Research
Background:
- Marfan syndrome (MFS) is an inherited connective tissue disorder linked to FBN1 gene mutations.
- Lung abnormalities are common in MFS, but their underlying mechanisms remain unclear.
- Interleukin-11 (IL11) is implicated in aortic disease in MFS and was investigated for its role in lung pathology.
Purpose of the Study:
- To investigate the role of IL11 in the pathogenesis of lung disease in a mouse model of Marfan syndrome (MFS).
- To determine if inhibiting IL11 signaling can mitigate lung abnormalities in MFS.
Main Methods:
- Histological and molecular analysis of lungs from Fbn1(C1041G/+) mice (a mouse model of MFS).
- Immunohistochemistry to identify IL11-expressing cells in reporter mice.
- Evaluation of IL11 inhibition effects using genetic knockout (IL11RA) and pharmacologic antibody treatments in MFS mice.
Main Results:
- MFS mouse lungs exhibited progressive airspace enlargement, inflammation, and fibrosis, with increased expression of proinflammatory genes and matrix metalloproteinases (MMPs).
- IL11 levels were elevated in MFS lungs, localized to smooth muscle, endothelial cells, and fibroblasts.
- Genetic or pharmacologic inhibition of IL11 signaling reduced emphysema, fibrosis, and inflammation, associated with decreased ERK1/2 signaling and MMP expression.
Conclusions:
- IL11 plays a causative role in lung disease development in the mouse model of Marfan syndrome.
- This study reveals a common IL11-driven mechanism for both lung and aortic disease in MFS.
- Inhibition of IL11 signaling presents a potential therapeutic strategy for treating multiorgan complications in Marfan syndrome.
