STAT3 Inhibition Partly Abolishes IL-33–Induced Bone Marrow–Derived Monocyte Phenotypic Transition into Fibroblast Precursor and Alleviates Experimental Renal Interstitial Fibrosis

Zhu, Fengge; Bai, Xueyuan; Hong, Quan; Cui, Shaoyuan; Wang, Xu; Xiao, Fengjun; Li, Jin; Zhang, Li; Dong, Zheyi; Wang, Yong; Cai, Guangyan; Chen, Xiangmei

doi:10.4049/jimmunol.1801273

Cited by 10 publications

(7 citation statements)

References 32 publications

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“…Previous study showed that STAT3 inhibitor, S3I-301, reduced renal fibrosis in a mouse unilateral ureteral obstruction model 35 . Furthermore, the novel STAT3 inhibitor BP-1-102 has been reported to alleviate renal interstitial fibrosis through the inhibition of bone marrow-derived monocyte transition into fibroblast precursors 24 . In cardiovascular diseases, specific STAT3 inhibition has been shown to not only downregulate IL-6induced collagen synthesis significantly but also effectively regresses the pressure overload-induced cardiac hypertrophy through reducing the fibrosis process 36 .…”

Section: Discussionmentioning

confidence: 99%

“…It is proved that BP-1-102 not only blocks the pathways of JAK2/STAT3 and NF-κB, but also targets Bcl-xL (an important protein involved in the cross talk of apoptosis and autophagy) 23 . Furthermore, BP-1-102 has been shown to have significant effects in several disease models [22][23][24] . However, the effect of BP-1-102 on vascular inflammation and AAA progression has not been reported.…”

Section: Introductionmentioning

confidence: 99%

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A novel STAT3 inhibitor attenuates angiotensin II-induced abdominal aortic aneurysm progression in mice through modulating vascular inflammation and autophagy

Cheng

Zhao

et al. 2020

Cell Death Dis

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Abdominal Aortic aneurysm (AAA) is associated with chronic inflammation, cells apoptosis, and impairment of autophagy. BP-1-102, a novel potent STAT3 inhibitor, has been recently reported to significantly block inflammationrelated signaling pathways of JAK2/STAT3 and NF-κB, as well as regulate autophagy. However, its role in vascular inflammation and AAA progression remains to be elucidated. In the present study, the effect and potential mechanisms of BP-1-102 on angiotensin II (AngII) induced AAA in ApoE −/− mice were investigated. AAA was induced in ApoE −/− mice with infusion of AngII for 28 days. BP-1-102 was administrated orally to mice every other day. Mice were sacrificed on day 7, day 14, and day 28 to evaluate the treatment effects. BP-1-102 markedly decreased AAA incidence and aortic diameter, maintained elastin structure and volume, reduced the expression of pro-inflammatory cytokines and MMPs, and inhibited inflammatory cells infiltration. Moreover, BP-1-102 dramatically reduced the expression of JAK2, p-STAT3, p-NF-κB, and Bcl-xL but maintained the expression of LC3B and Beclin in AAA tissues. In vitro, vascular smooth muscle cells (VSMCs) were treated with AngII and/or BP-1-102 at indicated time and concentration. BP-1-102 inhibited AngII-induced JAK2/STAT3 and NF-κB signaling activation and maintained autophagy-related proteins expression in VSMCs. Taken together, our findings suggest that BP-1-102 inhibits vascular inflammation and AAA progression through decreasing JAK2/STAT3 and NF-κB activation and maintaining autophagy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A novel STAT3 inhibitor attenuates angiotensin II-induced abdominal aortic aneurysm progression in mice through modulating vascular inflammation and autophagy

Cheng

Zhao

et al. 2020

Cell Death Dis

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“…It is possible that IL-33 recruits bone marrow-derived fibroblasts and inflammatory cells into the kidney, thereby producing proinflammatory factors and profibrotic molecules (Liang et al, 2017). Similarly, Zhu et al found that IL-33 induced the phenotypic transformation of bone marrow-derived monocytes into fibroblasts in a dosedependent manner, thereby leading to a marked increase in the expression of α-SMA and fibronectin (Zhu et al, 2019).…”

Section: Mechanisms Of Il33/st2 Involvement In Renal Fibrosismentioning

confidence: 98%

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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“…This is supported by other reports showing that epithelial STAT3 promotes type 2 inflammation in the lungs in response to HDM in mice 26 , and that pharmacological blockade of STAT3 inhibits both IL-13 and IL-17A responses to HDM 27 . As STAT3 has been reported to act as a transcriptional repressor [40][41][42] , in addition to several reports demonstrating that IL-33 activates STAT3 29,30,43 , we postulated a role for an IL-33-STAT3 axis in inhibiting dectin-1 expression in epithelial cells. Our data shows that impairing STAT3 function enhances dectin-1 gene expression, and thus establishes STAT3 as repressor of dectin-1.…”

Section: Discussionmentioning

confidence: 59%

Epigenetic regulation of epithelial dectin-1 through an IL-33-STAT3 axis in allergic disease

Yong¹,

Gour

Sharma³

et al. 2020

Preprint

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Allergic diseases arise in susceptible individuals in part because of decrements in protective pathways. The mechanism by which these anti-inflammatory molecules become repressed remains unclear. We have previously reported that epithelial dectin-1 prevents aberrant type 2 responses and is downregulated in the epithelium of allergic patients. Here we report that dectin-1 is constitutively expressed by the respiratory epithelium in humans, and that IL-33 specifically acts as a repressor of dectin-1. Mechanistically, this occurs via IL-33-dependent STAT3 activation and the subsequent repression of the dectin-1 gene, CLEC7A. We have identified a novel enhancer region upstream of the proximal promoter of CLEC7A that is only accessible in epithelial cells, but not in hematopoietic cells. Epigenetic repression of CLEC7A through this newly identified locus, downstream of an aberrant IL-33-STAT3 axis, occurs in the epithelium of allergic individuals. Collectively, our data identify a mechanism of epigenetic fine-tuning of dectin-1 expression in epithelial cells that may participate in allergenicity.

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STAT3 Inhibition Partly Abolishes IL-33–Induced Bone Marrow–Derived Monocyte Phenotypic Transition into Fibroblast Precursor and Alleviates Experimental Renal Interstitial Fibrosis

Cited by 10 publications

References 32 publications

A novel STAT3 inhibitor attenuates angiotensin II-induced abdominal aortic aneurysm progression in mice through modulating vascular inflammation and autophagy

A novel STAT3 inhibitor attenuates angiotensin II-induced abdominal aortic aneurysm progression in mice through modulating vascular inflammation and autophagy

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

Epigenetic regulation of epithelial dectin-1 through an IL-33-STAT3 axis in allergic disease

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