IL11 (Interleukin-11) Causes Emphysematous Lung Disease in a Mouse Model of Marfan Syndrome

Abstract

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 Fbn1 C1041G/+ 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 Fbn1 C1041G/+ : Il11 EGFP/+ 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 ( Fbn1 C1041G/+ : 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 Fbn1 C1041G/+ : Il11 EGFP/+ reporter strain and in fibroblasts, in older mice. In mMFS mice, genetic ( Fbn1 C1041G/+ : 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.

Poglut2/3 double knockout in mice results in neonatal lethality with reduced levels of fibrillin in lung tissues

“…1 D ). Similar defects in elastic fibers were described for Fbn1 mgR/mgR , Fbn1 C1041G/+ , Ltbp4 −/− , and Fbln5 −/− mutants ( 24 , 25 , 26 , 27 ). At embryonic day (E) 18.5, Poglut2/3 DKOs were viable and present at the expected Mendelian ratio ( Table 1 ).…”

“…3 , L and P ), which could reflect either regional sampling differences or a defect in late gestation terminal bronchiole branching or saccule morphogenesis. Airspace enlargement was also reported for Fbn1 mgR/mgR and FBN1 C1041G/+ mouse models ( 25 , 26 , 41 ). The shared structural abnormalities raise the possibility that the Poglut2/3 DKO impacted fibrillin levels.…”

Gingival Fibroblasts Are Sensitive to Oral Cell Lysates Indicated by Their IL11 Expression

“…For instance, fibroblast-specific IL11 transgene expression causes heart and kidney fibrosis and organ failure, whereas the genetic deletion of the interleukin 11 receptor alpha chain 1 protects against disease [49]. Moreover, IL11 is a critical driver of cardiovascular fibrosis [20], lung abnormalities [21,50], kidney injury and renal repair [19], and liver disease [23]. Considering the skull, mice lacking IL11 do not have craniosynostosis, and have normal long bone mass, suggesting that IL11 is not relevant in bone development [51]-but IL11 may play a key role in bone regeneration.…”

Understanding interleukin 11 as a disease gene and therapeutic target

“…The scientific community working on lung fibrosis was quick to embrace the idea that IL11 is an important pro-fibrotic factor and a number of publications have validated and extended findings: 2020, IL11/ERK signalling is important for senescence of lung cells [ 68 ] and fibroblast-specific expression of IL11 causes lung fibro-inflammation [ 140 ]; 2021, IL11 expression is associated with lung fibrosis in patients with rheumatoid arthritis [ 153 ], replication of IL11 up-regulation and its effects in bleomycin injury and HPS [ 154 ]; 2022, nanoparticle delivery of siRNA against Il11 reduces lung fibrosis in the bleomycin mouse model [ 155 ], IL11 contributes to pulmonary artery remodelling and fibrosis in pulmonary hypertension [ 90 ], therapeutic targeting of IL11 reduces lung fibro-inflammation due to silica particle inhalation [ 156 ]; 2023, anti-IL11 reduces emphysematous disease in a mouse model of Marfan syndrome [ 157 ], IL11 disrupts alveolar epithelial cell repair functions by causing EMT [ 103 , 104 ], IL11 is elevated in interstitial lung disease in systemic sclerosis [ 158 , 159 ] and IL11 contributes to lung fibrosis in patients with SARS-COV-2 [ 160 , 161 ].…”

“…In Marfan Syndrome, IL11 is up-regulated in VSMCs in the aorta and the lung and in this instance IL11 expression is likely due to increased TGFβ activity, which defines Marfan syndrome [ 157 , 178 ]. In a mouse model of Marfan syndrome, anti-IL11 therapy reduced aortic dilation and emphysema of the lungs [ 157 , 178 ].…”