Amphiregulin Confers Regulatory T Cell Suppressive Function and Tumor Invasion via the EGFR/GSK-3β/Foxp3 Axis

Wang, Sihua; Zhang, Yuan; Wang, Yan; Ye, Ping; Li, Jun; Li, Hua-Bin; Ding, Qingqing; Xia, Jiahong

doi:10.1074/jbc.m116.717892

Cited by 111 publications

(91 citation statements)

References 46 publications

(49 reference statements)

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“…The presence of amphiregulin enhanced the suppressive capacity of Tregs, but had no influence on the overall proliferation or survival of Tregs [55, 57]. Further evidence to support this result demonstrated that amphiregulin affected posttranslational regulation of Foxp3 expression through EGFR/GSK-3β signalling, which could lead to Foxp3 protein degradation in Tregs [61]. These observations support a positive feedback loop, whereby amphiregulin produced by Tregs promote tissue repair, and autocrine or paracrine amphiregulin signals activate Treg function by the EGFR pathway.…”

Section: Functional Molecules Expressed or Produced By ‘Repair’ Tregsmentioning

confidence: 56%

‘Repair’ Treg Cells in Tissue Injury

Zhang

Feng

et al. 2017

Cell Physiol Biochem

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Studies in mice and humans have elucidated an important role for Tregs in promoting tissue repair and restoring tissue integrity. Emerging evidence has revealed that Tregs promoted wound healing and repair processes at multiple tissue sites, such as the heart, liver, kidney, muscle, lung, bone and central nervous system. The localization of repair Tregs in the lung, muscle and liver exhibited unique phenotypes and functions. Epidermal growth factor receptor, amphiregulin, CD73/CD39 and keratinocyte growth factor are important repair factors that are produced or expressed by repair Tregs; these factors coordinate with parenchymal cells to limit injury and promote repair. In addition, repair Tregs can be modulated by IL-33/ST2, TCR signals and other cytokines in the context of injured microenvironment cues. In this review, we provide an overview of the emerging knowledge about Treg-mediated repair in damaged tissues and organs.

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Section: Functional Molecules Expressed or Produced By ‘Repair’ Tregsmentioning

confidence: 56%

‘Repair’ Treg Cells in Tissue Injury

Zhang

Feng

et al. 2017

Cell Physiol Biochem

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“…Further, Areg plays an important role in skeletal muscle regeneration, as its absence hampers wound repair (16). Functionally, Areg can directly stimulate satellite cells as well as enhance the suppressive capacity of Tregs (16, 34, 35). We asked whether treatment with Areg to chronically infected mice improved measures of function and inflammation.…”

Section: Resultsmentioning

confidence: 99%

“…However, in other systems Areg signaling enhances the suppressive capacity of Tregs as well as resolves injury and inflammation during infection (16, 34, 35). Consistent with its ability to act on satellite cells, we show that therapeutic administration of Areg leads to an enhanced myogenic molecular profile as evidenced by increased whole-tissue expression of the satellite cell specific marker Pax7 , as well as markers of myotube activation and differentiation, Myf5 and Myog , respectively.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Administration of IL-10 and Amphiregulin Alleviates Chronic Skeletal Muscle Inflammation and Damage Induced by Infection

2018

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Maintenance of tissue integrity in skeletal muscle requires the immunomodulatory and regenerative functions of muscle-resident regulatory T cells (Tregs). Chronic skeletal muscle infections, such as with Toxoplasma gondii disrupt normal immuno-regulatory networks and lead to pathogenic changes in Treg function. Specifically, Tregs during chronic T. gondii infection reinforce an inflammatory macrophage bias that exacerbates injury in skeletal muscle. In this study, we investigated whether the aberrations in skeletal muscle Treg function during chronic infection could be overcome by treatment with Treg-related factors associated with enhanced muscle regeneration during sterile injury. We show treatment of chronically infected mice with the Treg promoting therapies, interleukin-2 complexed with anti-IL-2 antibody or interleukin-33 (IL-33), did not restore macrophage dynamics or muscle function, respectively, in vivo. However supplementation of known Treg-derived factors, interleukin-10 (IL-10) and amphiregulin (Areg) improved muscle function and skewed macrophages toward a restorative phenotype in the presence of chronic infection. These shifts in macrophage phenotype are coupled with enhanced physiologic parameters of regeneration. Together, these data suggest that while Treg-mediated immuno-regulation is compromised during chronic skeletal muscle infection, supplementation of canonical Treg-derived factors such as IL-10 and Areg can restore immunologic balance and enhance muscle repair.

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“…The function of Tregs is critically linked with sustained expression of the transcription factor forkhead box protein P3 (Foxp3) and AREG/EGFR signaling was found to stabilize Foxp3 expression in Tregs thereby preserving Treg function during inflammation [44]. In addition to the direct regulation of Tregs by AREG, it was shown that a functionally distinct Treg subset expresses AREG upon activation [46], suggesting an autocrine feedback loop to further maintain Treg function independently of exogenous AREG.…”

Section: Areg and Tregsmentioning

confidence: 99%

“…One recently described mechanism by which hepatocarcinoma cells improve immunosuppressive intratumoral Treg function is via release of AREG [43]. During inflammation, activated Tregs up-regulate expression of EGFR and AREG/EGFR signaling was found to be crucial for effective Treg function in lung and gastric cancer [44]. In HBV infection, EGFR + Tregs responded to increased AREG expression by potent inhibition of anti-viral CD8 + T cells resulting in immune tolerance and persistent HBV infection [45].…”

Section: Areg and Tregsmentioning

confidence: 99%

Potential Involvement of the ILC2-Regulatory T Cell - Amphiregulin Axisin Liver Cancer Development: Novel Concepts for Immunotherapy of Hepatocellular Carcinoma

Neumann¹,

Ochel²,

Tiegs³

2017

J Clin Cell Immunol

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Hepatocellular carcinoma (HCC) is the most common primary liver tumor and its incidence is increasing. Since this type of cancer is largely resistant to systemic therapies, there is urgent need to identify cellular and molecular pathways involved in the pathogenesis of HCC. Recent evidence implicates inflammation-induced, immune cellderived amphiregulin (AREG) about interactions between immune cells of the innate and adaptive immune system by AREG in HCC development. We postulate an immunological network with pro-tumorigenic activity comprising AREG, type 2 innate lymphoid cells and regulatory T cells that might constitute a promising target for novel cancer immunotherapies.

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Amphiregulin Confers Regulatory T Cell Suppressive Function and Tumor Invasion via the EGFR/GSK-3β/Foxp3 Axis

Cited by 111 publications

References 46 publications

‘Repair’ Treg Cells in Tissue Injury

‘Repair’ Treg Cells in Tissue Injury

Therapeutic Administration of IL-10 and Amphiregulin Alleviates Chronic Skeletal Muscle Inflammation and Damage Induced by Infection

Potential Involvement of the ILC2-Regulatory T Cell - Amphiregulin Axisin Liver Cancer Development: Novel Concepts for Immunotherapy of Hepatocellular Carcinoma

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