Inhibiting Interleukin 11 Signaling Reduces Hepatocyte Death and Liver Fibrosis, Inflammation, and Steatosis in Mouse Models of Nonalcoholic Steatohepatitis

Widjaja, Anissa A.; Singh, Brijesh Kumar; Adami, Eleonora; Sivakumar, V.; Dong, Jinqiao; D’Agostino, G.; Ng, Benjamin; Lim, Wei‐Wen; Tan, Jessie; Paleja, Bhairav; Tripathi, Madhulika; Lim, Sze Yun; Shekeran, Shamini Guna; Chothani, Sonia; Rabes, Anne; Sombetzki, Martina; Bruinstroop, Eveline; Min, Lio Pei; Sinha, Rohit Anthony; Albani, Salvatore; Yen, Paul M.; Schäfer, Sebastian; Cook, Stuart A.

doi:10.1053/j.gastro.2019.05.002

Cited by 203 publications

(324 citation statements)

References 48 publications

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“…Indeed, IL‐6 is known to signal predominantly via the JAK/STAT pathway (Taga & Kishimoto, ). However, recent work in fibroblasts found that IL‐11 causes sustained ERK activation, without physiologically relevant activation of STAT (Ng et al, ; Schafer et al, ; Widjaja, Sing, et al, ). It has also been shown that IL‐11 at high concentrations can activate STAT in transformed cell lines (Lu et al, ) and some primary cells, although some of these cell lines do not appear to express the IL‐11RA, which requires further study.…”

Section: Il‐11 Is An Il‐6 Family Cytokine With Distinct Biological Fumentioning

confidence: 99%

“…IL‐6RA has also been detected in transformed hepatic cells such as HepG2. In contrast, IL‐11RA is most highly expressed on stromal cells including fibroblasts, vascular smooth muscle cells, adipocytes, hepatic/pancreatic stellate cells, and pericytes, as wells as on polarized cells such as hepatocytes, alveolar epithelial cells, and kidney tubular epithelial cells (Ng et al, ; Schafer et al, ; Widjaja, Sing, et al, ).…”

Section: Il‐11 Is An Il‐6 Family Cytokine With Distinct Biological Fumentioning

confidence: 99%

“…Clones were then screened for neutralization activity using fibroblast transformation as a readout. Clones X203 (anti‐IL‐11) and X209 (anti‐IL‐11ra1) effectively blocked the fibrotic response in mice and human cells and were chosen for preclinical testing in mouse models (Ng et al, ; Widjaja, Singh, et al, ). Neutralizing anti‐IL‐11 antibodies markedly reduced the pro‐fibrotic effect of TGF‐β stimulation on atrial fibroblasts across a wide range of assays, including myofibroblast activation, ECM production, and gel contraction and cell migration (Ng et al, ; Schafer et al, ).…”

Section: Neutralizing Il‐11 Antibodies Are Anti‐fibroticmentioning

confidence: 99%

“…In animal models, clones X203 and/or X209 have been shown to prevent or reverse fibrosis in the lung and liver (Ng et al, ; Widjaja, Singh, et al, ). Studies investigating the effects of anti‐IL‐11 therapy on cardiac or renal fibrosis are ongoing and are expected to be reported in the near future.…”

Section: Neutralizing Il‐11 Antibodies Are Anti‐fibroticmentioning

confidence: 99%

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IL‐11 in cardiac and renal fibrosis: Late to the party but a central player

Corden

Adami

Sweeney

et al. 2020

British J Pharmacology

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Fibrosis is a pathophysiological hallmark of cardiorenal disease. In the heart, fibrosis leads to contractile dysfunction and arrhythmias; in the kidney, it is the final common pathway for many diseases and predicts end‐stage renal failure. Despite this, there are currently no specific anti‐fibrotic treatments available for cardiac or renal disease. Recently and unexpectedly, IL‐11 was found to be of major importance for cardiorenal fibroblast activation and fibrosis. In mouse models, IL‐11 overexpression caused fibrosis of the heart and kidney while genetic deletion of Il11ra1 protected against fibrosis and preserved organ function. Neutralizing antibodies against IL‐11 or IL‐11RA have been developed that have anti‐fibrotic activity in human fibroblasts and protect against fibrosis in murine models of disease. While IL‐11 biology has been little studied and, we suggest, largely misunderstood, its autocrine activity in myofibroblasts appears non‐redundant for fibrosis, which offers new opportunities to better understand and potentially target cardiorenal fibrosis.

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Section: Il‐11 Is An Il‐6 Family Cytokine With Distinct Biological Fumentioning

confidence: 99%

Section: Il‐11 Is An Il‐6 Family Cytokine With Distinct Biological Fumentioning

confidence: 99%

Section: Neutralizing Il‐11 Antibodies Are Anti‐fibroticmentioning

confidence: 99%

Section: Neutralizing Il‐11 Antibodies Are Anti‐fibroticmentioning

confidence: 99%

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IL‐11 in cardiac and renal fibrosis: Late to the party but a central player

Corden

Adami

Sweeney

et al. 2020

British J Pharmacology

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“…Both these cellular transitions are characterized by extracellular matrix (ECM) production, cell proliferation, invasion and migration. They can also be triggered by the same extracellular cues including TGFB family members [1,7].We recently identified IL11 as a critical driver of fibroblast activation in the cardiovascular system, liver and lung downstream of a variety of pro-fibrotic factors including TGFB1 [8][9][10].In a study from 1999, IL11 was also found to be secreted by vascular SMCs (VSMCs) in response to pathogenic stimuli, including interleukin 1 alpha (IL1A), TGFB and tumor necrosis factor (TNF) [11]. Although IL11 is upregulated in systemic sclerosis [6], TNFresistant ulcerative colitis [12,13] and asthma [14] and despite SMCs being a source of IL11[11], the effect of IL11 function in SMC biology has not been studied.…”

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confidence: 99%

Interleukin 11 expression causes murine inflammatory bowel disease

Lim

Widjaja

et al. 2019

Preprint

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Interleukin 11 (IL11) is a profibrotic cytokine, secreted by myofibroblasts and damaged epithelial cells. Smooth muscle cells (SMCs) also secrete IL11 under pathological conditions and express the IL11 receptor. Here we examined the effects of SMC-specific, conditional expression of murine IL11 in a transgenic mouse (Il11 SMC ). Within days of transgene activation, Il11 SMC mice developed loose stools and progressive bleeding and rectal prolapse, which was associated with a 65% mortality by two weeks. The bowel of Il11 SMC mice was inflamed, fibrotic and had a thickened wall, which was accompanied by activation of ERK and STAT3. In other organs, including heart, lung, liver, kidney and skin there was a phenotypic spectrum of fibro-inflammation, together with consistent ERK activation. To investigate further the importance of stromal-derived IL11 in the inflammatory bowel phenotype we used a second model with fibroblast-specific expression of IL11, the Il11 Fib mouse. This additional model largely phenocopied the Il11 SMC bowel phenotype. These data show that IL11 secretion from the stromal niche is sufficient to drive inflammatory bowel disease in mice. Given that IL11 expression in colonic stromal cells predicts anti-TNF therapy failure in patients with ulcerative colitis or Crohn's disease, we suggest IL11 as a therapeutic target for inflammatory bowel disease. Main textNon-striated smooth muscle cells (SMCs) line the walls of hollow organs and the vasculature. In adults, SMCs are not terminally differentiated and their cellular phenotype remains plastic. A variety of extracellular cues such as humoral factors, mechanical or oxidative stress and cell-cell interactions can induce a spectrum of cellular states ranging from contractile SMCs to highly synthetic and proliferative SMCs [1]. Synthetic SMCs are associated with a wide variety of vascular pathologies such as atherosclerosis or hypertension [1] and other disorders such as asthma [2] and inflammatory bowel disease (IBD) [3]. Many fibro-inflammatory diseases have a component, or are defined by, SMCdysfunction. This is exemplified by systemic sclerosis, which presents with global organ fibrosis and specific vascular abnormalities [4] and is characterized by elevated transforming growth factor beta (TGFB) 2 and interleukin 11 (IL11) expression in dermal stromal cells [5,6]. This co-occurrence of fibrosis and SMC dysfunction may in part be explained by molecular similarities of the fibrogenic fibroblast-to-myofibroblast conversion and the SMC contractile-to-synthetic phenotype switch. Both these cellular transitions are characterized by extracellular matrix (ECM) production, cell proliferation, invasion and migration. They can also be triggered by the same extracellular cues including TGFB family members [1,7].We recently identified IL11 as a critical driver of fibroblast activation in the cardiovascular system, liver and lung downstream of a variety of pro-fibrotic factors including TGFB1 [8][9][10].In a study from 1999, IL11 was also found to be secreted by ...

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Autologous Skin Fibroblast‐Based PLGA Nanoparticles for Treating Multiorgan Fibrosis

et al. 2022

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Fibrotic diseases remain a substantial health burden with few therapeutic approaches. A hallmark of fibrosis is the aberrant activation and accumulation of myofibroblasts, which is caused by excessive profibrotic cytokines. Conventional anticytokine therapies fail to undergo clinical trials, as simply blocking a single or several antifibrotic cytokines cannot abrogate the profibrotic microenvironment. Here, biomimetic nanoparticles based on autologous skin fibroblasts are customized as decoys to neutralize multiple fibroblast‐targeted cytokines. By fusing the skin fibroblast membrane onto poly(lactic‐co‐glycolic) acid cores, these nanoparticles, termed fibroblast membrane‐camouflaged nanoparticles (FNPs), are shown to effectively scavenge various profibrotic cytokines, including transforming growth factor‐β, interleukin (IL)‐11, IL‐13, and IL‐17, thereby modulating the profibrotic microenvironment. FNPs are sequentially prepared into multiple formulations for different administration routines. As a proof‐of‐concept, in three independent animal models with various organ fibrosis (lung fibrosis, liver fibrosis, and heart fibrosis), FNPs effectively reduce the accumulation of myofibroblasts, and the formation of fibrotic tissue, concomitantly restoring organ function and indicating that FNPs are a potential broad‐spectrum therapy for fibrosis management.

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Inhibiting Interleukin 11 Signaling Reduces Hepatocyte Death and Liver Fibrosis, Inflammation, and Steatosis in Mouse Models of Nonalcoholic Steatohepatitis

Cited by 203 publications

References 48 publications

IL‐11 in cardiac and renal fibrosis: Late to the party but a central player

IL‐11 in cardiac and renal fibrosis: Late to the party but a central player

Interleukin 11 expression causes murine inflammatory bowel disease

Autologous Skin Fibroblast‐Based PLGA Nanoparticles for Treating Multiorgan Fibrosis

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