IL-33 induces type-2-cytokine phenotype but exacerbates cardiac remodeling post-myocardial infarction with eosinophil recruitment, worsened systolic dysfunction, and ventricular wall rupture

Ghali, Rana; Habeichi, Nada; Kaplan, Abdullah; Tannous, Cynthia; Abidi, Emna; Bekdash, Amira; Farhat, Rima; Itani, Hana A.; Booz, George W.; Mallat, Ziad; Zouein, Fouad A.

doi:10.1042/cs20200402

Cited by 17 publications

(15 citation statements)

References 96 publications

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“…There are some limitations in this study that deserve acknowledgment. First, apart from its cardioprotective effects, continuous IL‐33 treatment has been observed to increase plasma IL‐5 levels and induce cardiac eosinophilic infiltration both in this and other studies (Abston et al, 2012; Choi et al, 2020; Ghali et al, 2020), which indicates a modification of immune system by IL‐33. However, the effects of these modifications on IL‐33‐derived cardio‐protection are unknown.…”

Section: Discussionsupporting

confidence: 61%

Interleukin‐33 alleviates diabetic cardiomyopathy through regulation of endoplasmic reticulum stress and autophagy via insulin‐like growth factor‐binding protein 3

Wang

Xie

et al. 2020

Journal Cellular Physiology

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Prolonged endoplasmic reticulum (ER) stress is the key driving force behind diabetic cardiomyopathy (DCM). Autophagy is extensively implicated in adaptive mechanisms for cell survival. Interleukin-33 (IL-33) is known to be a potent cardiac protector, but its roles in DCM, ER stress, and autophagy are currently unknown. We aimed to explore the effects of IL-33 on DCM and characterize the roles that ER stress and autophagy play in DCM. The effects of IL-33 on DCM, ER stress, and autophagy were characterized both in db/db mice and in palmitic acid (PA)-treated cardiomyocytes. The manipulators of ER stress and autophagy were used to clarify their roles in DCM remittance conferred by IL-33. Gene expression analysis was used to identify IL-33-dependent regulators of ER stress and autophagy. Both db/db mice and PA-treated cells presented with enhanced levels of ER stress, apoptosis, and lipid deposition, as well as impaired autophagy, all of which could be reversed by IL-33. Treatment with IL-33 improved the cardiac diastolic function of diabetic mice. Nonselective autophagy inhibitors, such as 3-methyladenine (3-MA) or wortmannin, abolished the protective effects of IL-33, resulting in an increase in both ER stress and apoptosis. Strikingly, insulin-like growth factor-binding protein 3 (IGFBP3) was identified as the gene most significantly differentially expressed between IL-33 and control groups. Knockdown of IGFBP3 expression, similar to the effect of nonselective autophagy inhibitors, resulted in high levels of ER stress, impaired autophagy, and apoptosis that were not rescued upon treatment with IL-33. IL-33 abates DCM by alleviating ER stress and promoting autophagy. IGFBP3 is essential for IL-33-induced ER stress resolution and autophagic enhancement during DCM.

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Section: Discussionsupporting

confidence: 61%

Interleukin‐33 alleviates diabetic cardiomyopathy through regulation of endoplasmic reticulum stress and autophagy via insulin‐like growth factor‐binding protein 3

Wang

Xie

et al. 2020

Journal Cellular Physiology

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“…As shown in Table 1, the role of this pathway in cardiac fibrosis is controversial. Sanada et al (2007) observed that the IL-33/ST2 pathway limits overall ventricular fibrosis, whereas Ghali et al (2020) reported IL-33 aggravated the deterioration of cardiac function and cardiac remodeling. In fact, it is associated with activation of myofibroblasts and an increase in the pro-fibrotic markers, such as connective tissue growth factor (CTGF) and TGF-β (Ghali et al, 2020).…”

Section: The Role Of Il-33/st2 Pathway In Renal Fibrosismentioning

confidence: 99%

“…Sanada et al (2007) observed that the IL-33/ST2 pathway limits overall ventricular fibrosis, whereas Ghali et al (2020) reported IL-33 aggravated the deterioration of cardiac function and cardiac remodeling. In fact, it is associated with activation of myofibroblasts and an increase in the pro-fibrotic markers, such as connective tissue growth factor (CTGF) and TGF-β (Ghali et al, 2020). Overall, in majority of fibrotic diseases, this pathway mainly promotes inflammatory responses and facilitates organ fibrosis, ultimately leading to organ dysfunction.…”

Section: The Role Of Il-33/st2 Pathway In Renal Fibrosismentioning

confidence: 99%

“…Additionally, IL-33 has been associated with vascular disease dysfunction (Gungor et al, 2017). It has been reported that IL-33 effectively activates the type 2 cytokine milieu in the damaged heart and is associated with the deterioration of cardiac function as well as cardiac remodeling (Ghali et al, 2020). Furthermore, serum IL-33 and sST2 levels were elevated in patients with chronic HF (Zhang et al, 2012), and they continue to increase with the degradation of cardiac function (Xiang et al, 2021).…”

Section: The Potential Value Of the Il-33/ St2 Pathway For Renal Fibrosismentioning

confidence: 99%

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Interleukin-33/ Suppression of Tumorigenicity 2 in Renal Fibrosis: Emerging Roles in Prognosis and Treatment

Tan

Jing

2022

Front. Physiol.

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Chronic kidney disease (CKD) is a major public health problem that affects more than 10% of the population worldwide and has a high mortality rate. Therefore, it is necessary to identify novel treatment strategies for CKD. Incidentally, renal fibrosis plays a central role in the progression of CKD to end-stage renal disease (ESRD). The activation of inflammatory pathways leads to the development of renal fibrosis. In fact, interleukin-33 (IL-33), a newly discovered member of the interleukin 1 (IL-1) cytokine family, is a crucial regulator of the inflammatory process. It exerts pro-inflammatory and pro-fibrotic effects via the suppression of tumorigenicity 2 (ST2) receptor, which, in turn, activates other inflammatory pathways. Although the role of this pathway in cardiac, pulmonary, and hepatic fibrotic diseases has been extensively studied, its precise role in renal fibrosis has not yet been completely elucidated. Recent studies have shown that a sustained activation of IL-33/ST2 pathway promotes the development of renal fibrosis. However, with prolonged research in this field, it is expected that the IL-33/ST2 pathway will be used as a diagnostic and prognostic tool for renal diseases. In addition, the IL-33/ST2 pathway seems to be a new target for the future treatment of CKD. Here, we review the mechanisms and potential applications of the IL-33/ST2 pathway in renal fibrosis; such that it can help clinicians and researchers to explore effective treatment options and develop novel medicines for CKD patients.

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“…Among these increased inflammatory gene products are several pro-inflammatory cytokines which play a detrimental role in cardiac physiology (Fig. 5F) (13, 21, 26, 73). Importantly, we also show an increase in plasma levels of TNF-αand IL-6 (Fig.…”

Section: Resultsmentioning

confidence: 99%

Adipocyte deletion of the RNA binding protein HuR induces cardiac hypertrophy and fibrosis

Guarnieri

Anthony

Gozdiff

et al. 2021

Preprint

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Adipose tissue continues to gain appreciation for its broad role as an endocrine organ, and disruptions in adipose tissue homeostasis plays a central role in cardiovascular physiology. We have previously shown that expression of the RNA binding protein HuR in adipose tissue mediates energy expenditure, but the potential cardiovascular impacts of this finding have not been explored. We show here that adipose tissue-specific deletion of HuR (Adipo-HuR-/-) is sufficient to induce the spontaneous development of cardiac hypertrophy and fibrosis. Hearts from Adipo-HuR-/- mice have increased left ventricular (LV) ejection fraction, rate of pressure generation, and LV posterior wall thickness that is accompanied by an increase in LV/body weight ratio and hypertrophic gene expression. Furthermore, Adipo-HuR-/- hearts display increased fibrosis by picrosirius red staining and periostin expression. To identify underlying mechanisms, we applied both RNA-seq and weighted gene co-expression network analysis (WGCNA) to define HuR-dependent changes in gene expression as well as significant relationships between adipose tissue gene expression and LV mass. RNA-seq results demonstrate a significant increase in pro-inflammatory gene expression in the subcutaneous white adipose tissue (scWAT) from Adipo-HuR-/- mice that is accompanied by an increase in serum levels of both TNF-α and IL-6. WGCNA identified a significant enrichment in inflammation, apoptosis/cell death, and vesicle-mediated transport genes among those whose expression most significantly associated with CVD in Adipo-HuR-/-. In conclusion, we demonstrate that the loss of HuR expression in adipose tissue promotes the development of cardiac hypertrophy and fibrosis, potentially through modulation of inflammation and vesicle-mediated transport in scWAT.NEW AND NOTEWORTHYThis work demonstrates the spontaneous development of cardiac hypertrophy and fibrosis upon adipose tissue-specific deletion of the RNA binding protein HuR that appears to be mechanistically driven by HuR-dependent changes in inflammatory and extracellular vesicle transport mediating genes in the subcutaneous white adipose tissue. These results suggest that loss of HuR expression in adipose tissue in obesity, as demonstrated in mouse and humans by our group and others, may contribute to obesity-mediated CVD.

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IL-33 induces type-2-cytokine phenotype but exacerbates cardiac remodeling post-myocardial infarction with eosinophil recruitment, worsened systolic dysfunction, and ventricular wall rupture

Cited by 17 publications

References 96 publications

Interleukin‐33 alleviates diabetic cardiomyopathy through regulation of endoplasmic reticulum stress and autophagy via insulin‐like growth factor‐binding protein 3

Interleukin‐33 alleviates diabetic cardiomyopathy through regulation of endoplasmic reticulum stress and autophagy via insulin‐like growth factor‐binding protein 3

Interleukin-33/ Suppression of Tumorigenicity 2 in Renal Fibrosis: Emerging Roles in Prognosis and Treatment

Adipocyte deletion of the RNA binding protein HuR induces cardiac hypertrophy and fibrosis

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