Hepatocyte-specific IL11 cis-signaling drives lipotoxicity and underlies the transition from NAFLD to NASH

Dong, Jinqiao; Sivakumar, V.; Adami, Eleonora; Singh, Brijesh Kumar; Chothani, Sonia; Ng, Benjamin; Lim, Wei‐Wen; Zhou, Jin; Tripathi, Madhulika; Ko, Nicole S. J.; Shekeran, Shamini Guna; Tan, Jessie; Lim, Sze Yun; Wang, Mao; Lio, Pei Min; Yen, Paul M.; Schäfer, Sebastian; Cook, Stuart A.; Widjaja, Anissa A.

doi:10.1038/s41467-020-20303-z

Cited by 88 publications

(122 citation statements)

References 42 publications

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“…In conclusion, loss of IL11 signaling due to mutation in either Il11 or Il11RA1 is protective against lung fibrosis that relates to reduced autocrine IL11 activity in myofibroblasts 14 , 30 . However, the craniosynostosis and bone phenotypes seen in Il11RA1 deficient mice are not seen in Il11 − / − mice, suggesting that developmental, STAT3-related bone effects are not due to defective IL11 signaling per se and instead, specific to Il11RA1 LOF.…”

Section: Discussionmentioning

confidence: 92%

Similarities and differences between IL11 and IL11RA1 knockout mice for lung fibro-inflammation, fertility and craniosynostosis

Widjaja

Sivakumar

et al. 2021

Sci Rep

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Loss of function (LOF) in IL11RA infers IL11 signaling as important for fertility, fibrosis, inflammation and incompletely penetrant craniosynostosis. The impact of LOF in IL11 has not been characterized. We generated IL11 knockout (Il11−/−) mice that are born in expected ratios and have normal hematological profiles. Lung fibroblasts from Il11−/− mice are resistant to pro-fibrotic stimulation with TGFβ1. Following bleomycin-induced lung injury, Il11−/− mice are protected from pulmonary fibrosis and exhibit lesser ERK, STAT3 and NF-kB activation, reduced Il1b, Timp1, Ccl2 and diminished IL6 expression, both at baseline and after injury: placing Il11 activity upstream of IL6 in this model. Il11−/− female mice are infertile. Unlike Il11ra1−/− mice, Il11−/− mice do not have craniosynostosis, have normal long bone mass and reduced body weights. These data further establish the role of IL11 signaling in lung fibrosis while suggesting that bone development abnormalities can be associated with mutation of IL11RA but not IL11, which may have implications for therapeutic targeting of IL11 signaling.

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Section: Discussionmentioning

confidence: 92%

Similarities and differences between IL11 and IL11RA1 knockout mice for lung fibro-inflammation, fertility and craniosynostosis

Widjaja

Sivakumar

et al. 2021

Sci Rep

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“…Accumulating evidence has suggested that the pathological remodeling response is coordinated with oxidative stress, inflammation, apoptosis and numerous signaling pathways. Jinrui Dong's study showed that IL-11 activity causes hepatocyte death through NOX4-derived ROS, activation of ERK, JNK and caspase-3, impaired mitochondrial function and reduced fatty acid oxidation [ 51 ]. Anissa A. Widjaja's study discovered an unexpected proinflammatory role for IL-11 in the liver [ 49 ].…”

Section: Discussionmentioning

confidence: 99%

Lutein attenuates angiotensin II- induced cardiac remodeling by inhibiting AP-1/IL-11 signaling

et al. 2021

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Rationale Oxidative stress plays a critical role in the development of cardiac remodeling and heart failure. Lutein, the predominant nonvitamin A carotenoid, has been shown to have profound effects on oxidative stress. However, the effect of lutein on angiotensin II (Ang II)-induced cardiac remodeling and heart failure remains unknown. Objective The aim of this study was to determine whether lutein is involved in cardiac remodeling and to elucidate the underlying molecular mechanisms. Methods and results In vitro experiments with isolated neonatal rat cardiomyocytes (NRCMs) and cardiac fibroblasts (CFs) revealed that lutein significantly attenuated Ang II-induced collagen expression in CFs, and cardiomyocyte hypertrophy. The Ang II-induced increases in superoxide generation, inflammation and apoptosis in cultured CFs were strikingly prevented by lutein. In vivo, fibrosis, hypertrophic cardiomyocyte and superoxide generation were analyzed, and lutein was demonstrated to confer resistance to Ang II-induced cardiac remodeling in mice. Mechanistically, RNA sequencing revealed that interleukin-11 (IL-11) expression was significantly upregulated in mouse hearts in response to Ang II infusion and was significantly suppressed in the hearts of lutein-treated mice. Furthermore, IL-11 overexpression blocked the effects of lutein on fibrosis and oxidative stress in CFs and impaired the protective effect of lutein on cardiac remodeling. Notably, we discovered that lutein could reduce Ang II-induced IL-11 expression, at least partly through the regulation of activator protein (AP)-1 expression and activity. Conclusions Lutein has potential as a treatment for cardiac remodeling and heart failure via the suppression of IL-11 expression.

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“…While earlier reports demonstrated that recombinant human IL-11 protects from hepatocyte damage induced by oxidative stress, drugs, or ischemia/reperfusion [51][52][53][54], more recent reports show that IL-11 rather promotes liver damage via ROS production [20], activates HSCs [19,20], and hence, promotes liver fibrosis in the setting of chronic liver disease. Similarly, OSM was shown to prevent hepatocyte damage by oxidative stress [55][56][57] and to promote hepatic fibrosis by upregulation of TGFβ and PDGF in hepatic macrophages [58], and by stimulating myofibroblast migration [59].…”

Section: Physiological Role Of Il-6 Family Cytokines In the Livermentioning

confidence: 98%

“…During chronic liver disease also senescent hepatocytes and BECs secrete IL-6 (see also below), while OSM is also secreted by hepatic progenitor cells [18]. IL-11 is secreted by activated HSCs [19] [20] and lipidloaded hepatocytes [20] in the course of non-alcoholic fatty liver disease (NAFLD).…”

Section: The Cellular Landscape Of Il-6 Family Cytokine Sender and Receiver In The Livermentioning

confidence: 99%

The two facets of gp130 signalling in liver tumorigenesis

2021

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The liver is a vital organ with multiple functions and a large regenerative capacity. Tumours of the liver are the second most frequently cause of cancer-related death and develop in chronically inflamed livers. IL-6-type cytokines are mediators of inflammation and almost all members signal via the receptor subunit gp130 and the downstream signalling molecule STAT3. We here summarize current knowledge on how gp130 signalling and STAT3 in tumour cells and cells of the tumour micro-environment drives hepatic tumorigenesis. We furthermore discuss very recent findings describing also anti-tumorigenic roles of gp130/STAT3 and important considerations for therapeutic interventions.

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Hepatocyte-specific IL11 cis-signaling drives lipotoxicity and underlies the transition from NAFLD to NASH

Cited by 88 publications

References 42 publications

Similarities and differences between IL11 and IL11RA1 knockout mice for lung fibro-inflammation, fertility and craniosynostosis

Similarities and differences between IL11 and IL11RA1 knockout mice for lung fibro-inflammation, fertility and craniosynostosis

Lutein attenuates angiotensin II- induced cardiac remodeling by inhibiting AP-1/IL-11 signaling

The two facets of gp130 signalling in liver tumorigenesis

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