A Neutralizing IL-11 Antibody Improves Renal Function and Increases Lifespan in a Mouse Model of Alport Syndrome

Abstract

Background: Alport syndrome is a genetic disorder characterized by a defective glomerular basement membrane, tubulointerstitial fibrosis, inflammation, and progressive renal failure. IL-11 was recently implicated in fibrotic kidney disease but its role in Alport syndrome is unknown Methods: We determined IL-11 expression by molecular analyses and in an Alport syndrome mouse model. We assessed the effects of a neutralizing IL-11 antibody (X203) versus an IgG control in Col4a3-/- mice (lacking the gene encoding a type IV collagen component) on renal tubule damage, function, fibrosis, and inflammation. Effects on lifespan of X203, the IgG control, an angiotensin-converting enzyme inhibitor (ramipril), or ramipril+X203 were also studied. Results: In Col4a3 mice, as kidney failure advanced, renal IL-11 levels increased and IL-11 expression localized to tubular epithelial cells. The IL-11 receptor IL11RA is expressed in tubular epithelial cells and podocytes and is upregulated in tubular epithelial cells of Col4a3 mice. Administration of X203 reduced albuminuria, improved renal function, and preserved podocyte numbers and levels of key podocyte proteins that are reduced in Col4a3 mice; these effects were accompanied by reduced fibrosis and inflammation, attenuation of epithelial-tomesenchymal transition, and increased expression of regenerative markers. X203 attenuated pathogenic ERK and STAT3 pathways, which were activated in Col4a3 mice. Median lifespan of Col4a3 mice was prolonged 22% by ramapril, 44% with X203, and 99% with amipril+X203. Conclusions: In an Alport syndrome mouse model, renal IL-11 is upregulated, and neutralization of IL-11 reduces epithelial-to-mesenchymal transition, fibrosis, and inflammation, while improving renal function. Anti-IL-11 combined with ACE inhibition synergistically extends lifespan. This suggests that a therapeutic approach targeting IL-11 holds promise for progressive kidney disease in Alport syndrome.

Structures of the interleukin 11 signalling complex reveal dynamics of gp130 extracellular domains and the inhibitory mechanism of a cytokine variant

“…Critical pathological roles for dysregulated IL-11 have been identified in autoimmune diseases including arthritis, asthma, inflammatory bowel disease, multiple sclerosis, and systemic sclerosis 3,4,6,7,15,16 . In addition, IL-11 drives fibrotic complications of the gastrointestinal tract, heart, kidney, liver and lung [9][10][11][17][18][19][20][21] , and promotes the growth of several malignancies, including breast, lung, endometrial and gastrointestinal cancers [22][23][24][25][26] . Despite these emerging physiological and pathological roles, structural understanding of IL-11 signalling has remained limited.…”

“…Inhibition of IL-11 signalling has been shown to provide therapeutic benefit in models of arthritis, multiple sclerosis, neointimal hyperplasia, multiple fibrotic diseases, and gastrointestinal cancers [9][10][11]13,17,21,22,25,39,40 . Current IL-11 signalling inhibitors include IL-11 mutants 41,42 and antibodies against either IL-11 9,21,43 or IL-11Rα 11,[44][45][46] . However, mechanistic understanding of their modes of action is limited in the absence of detailed molecular understanding of the IL-11 signalling complex.…”

Hepatocyte Specific gp130 Signalling Underlies APAP Induced Liver Injury

“…Interleukin-11 (IL11) is a member of the IL6 family cytokine that has pathogenic activity in the liver [12,13]. However, IL11-stimulated STAT3 activity is also suggested to protect the liver: an injection of recombinant human IL11 (rhIL11) into mice reduces Concanavalin A-induced, T-cell-mediated hepatotoxicity and N-acetyl-p-aminophenol (APAP)-induced liver damage [14,15].…”

IL11 Activates Pancreatic Stellate Cells and Causes Pancreatic Inflammation, Fibrosis and Atrophy in a Mouse Model of Pancreatitis

“…We suggest that the elevated levels of IL11 in acinar cells in chronic pancreatitis could be linked with additional effects of IL11 in the pancreas, outside of the stroma. Indeed, there are emerging links between IL11 and epithelial cell dysfunction, notably epithelial-to-mesenchymal transition, in other organs such as the liver, kidney and lung [ 35 , 36 , 37 , 38 ]. We end by suggesting that therapies targeting IL11 signalling may be considered as a therapeutic approach for patients with pancreatitis.…”