Researchers at the MRC London Institute of Medical Sciences (LMS), National Heart Research Institute Singapore and Duke-National University of Singapore Medical School have shown inhibition of a protein called Interleukin-11 prevents the progression of Marfan Syndrome and Alport Syndrome in mice. 

Interleukin-11 (IL-11) is known to regulate the function of a wide range of cell types and to cause tissue scaring. Research has shown increased IL-11 activity occurs in a variety of cancers. It has also been implicated in fibrotic kidney disease, and signalling activity in the cells that line blood vessels has suggested IL-11 plays a role in artery disease.

Professor Stuart Cook, head of the LMS Cardiovascular Disease Mechanisms Group teamed up with researchers in Singapore to investigate the role of IL-11 in two genetic diseases; Marfan Syndrome (MFS), a rare disorder that affects multiple organs and can lead to fatal artery rupture. And Alport Syndrome, which is usually diagnosed in children who can later develop kidney disease and hearing loss.

To unpick the role IL-11 might be playing in MFS, researchers took an established mouse model of the syndrome, the Fbn1C1041G/+ mouse and crossed it with either a mouse that expressed green fluorescent labelled IL-11 or a mouse that does not express the IL-11 receptor. This gave them one MFS mouse model where IL-11 expression could be observed and another MFS mouse model that could no longer respond to IL-11 expression because it lacks the required receptor. They found the MFS mice had increased levels of IL-11 compared to healthy wildtype mice and that IL-11 expression was enriched in the cells that line blood vessels, particularly in the aorta. The MFS mice lacking the IL-11 receptor were found to have less inflammation and reduced aortic dilation. To test the therapeutic potential of IL-11, the researchers administered an antibody that blocked IL-11 signalling. They found this treatment appeared to reduce aortic dilation, inflammation and fibrosis in MFS mice. This supports inhibition of IL11, as a new approach for managing MFS.

For Alport Syndrome, the researchers utilised a model that mimics the human disease, the Col4a3-/- mouse. Researchers were able to show that as kidney failure progressed, expression of IL-11 increased specifically in the tubular epithelial cells of the mouse’s kidney. They also found that administering an antibody that blocks IL-11 activity improved the mouse’s kidney function, increased the expression of regenerative markers and prolonged lifespan. This suggests targeting IL-11 could hold promise as a treatment for progressive kidney disease in Alport syndrome.

Professor Stuart Cook, head of the LMS Cardiovascular Disease Mechanisms Research Group said: “It was surprising to find that IL-11 causes disease in patients with different genetic mutations and that inhibiting IL-11 with antibody drugs reduces both artery and kidney disease. If safe, anti-IL11 therapies might be considered in patients with Marfan or Alport syndrome, perhaps tested when combined with angiotensin converting enzyme inhibitor drugs.”

MFS affects around 1 in 5,000 people in the UK, which makes it rare. It is, however, one of the most common connective tissue disorders.

Approximately 1 in 5,000 people in the UK are living with Alport Syndrome.  The disease is the second highest cause of inherited chronic kidney disease (CKD) after polycystic kidney disease.

‘Inhibition of IL11 Signaling Reduces Aortic Pathology in Murine Marfan Syndrome’ was published in Circulation Research on 09 February 2022.

‘A Neutralizing IL-11 Antibody Improves Renal Function and Increases Lifespan in a Mouse Model of Alport Syndrome’ was published in the Journal of American Society of Nephrology in February 2022.

You can find out more about Professor Cook’s group research here on the LMS website.