CD39+ Fibroblasts Enhance Myofibroblast Activation by Promoting IL-11 Secretion in Hypertrophic Scars

Huang, Xin; Gu, Shuchen; Liu, Caiyue; Zhang, Liang; Zhang, Zewei; Zhao, Yixuan; Khoong, Yimin; Li, Haizhou; Gao, Yashan; Liu, Yunhan; Zi, Wenjie; Zhao, Deyu; Li, Qingfeng; Zan, Tao

doi:10.1016/j.jid.2021.07.181

Cited by 19 publications

(14 citation statements)

References 37 publications

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“…In addition, cytokines and cell adhesion molecules are also reported to play roles in ECM deposition, fibroblast differentiation, and cell migration. TGF- β -induced release of IL-11 is significantly upregulated in hypertrophic scars, which activates the enrichment of CD39+ fibroblasts within the upper dermis and secretes a large amount of ECM [ 53 ]. CD44 is a cell surface adhesion receptor that has been implicated in leukocyte recruitment, T cell extravasation, and hyaluronic acid metabolism.…”

Section: Regulation Of Fibroblasts In Wound Healing and Scar Formationmentioning

confidence: 99%

Fibroblasts in Scar Formation: Biology and Clinical Translation

Qian

Shan

Gong

et al. 2022

Oxidative Medicine and Cellular Longevity

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Scarring, which develops due to fibroblast activation and excessive extracellular matrix deposition, can cause physical, psychological, and cosmetic problems. Fibroblasts are the main type of connective tissue cells and play important roles in wound healing. However, the underlying mechanisms of fibroblast in reaching scarless wound healing require more exploration. Herein, we systematically reviewed how fibroblasts behave in response to skin injuries, as well as their functions in regeneration and scar formation. Several biocompatible materials, including hydrogels and nanoparticles, were also suggested. Moreover, factors that concern transformation from fibroblasts into cancer-associated fibroblasts are mentioned due to a tight association between scar formation and primary skin cancers. These findings will help us better understand skin fibrotic pathogenesis, as well as provide potential targets for scarless wound healing therapies.

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Section: Regulation Of Fibroblasts In Wound Healing and Scar Formationmentioning

confidence: 99%

Fibroblasts in Scar Formation: Biology and Clinical Translation

Qian

Shan

Gong

et al. 2022

Oxidative Medicine and Cellular Longevity

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“…IL11 was initially characterized as anti-inflammatory, anti-fibrotic and pro-regenerative based largely on experiments in which recombinant human IL11 (rhIL11) was administered to mouse models of disease [ 3 ]. However, species-matched IL11 was recently found to have ERK-dependent pro-fibrotic activity in fibroblasts [ 4 , 5 , 6 , 7 ], and it transpires that rhIL11 has unexpected activity in the mouse and paradoxically inhibits endogenous murine IL11 [ 8 ]. In mammals, IL11 is now largely accepted to be pro-fibrotic [ 9 ] and is increasingly viewed as anti-regenerative [ 8 , 10 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

IL11 Stimulates IL33 Expression and Proinflammatory Fibroblast Activation across Tissues

Widjaja

Chothani

Sivakumar

et al. 2022

IJMS

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Interleukin 11 (IL11) is upregulated in inflammatory conditions, where it is mostly believed to have anti-inflammatory activity. However, recent studies suggest instead that IL11 promotes inflammation by activating fibroblasts. Here, we assessed whether IL11 is pro- or anti-inflammatory in fibroblasts. Primary cultures of human kidney, lung or skin fibroblasts were stimulated with IL11 that resulted in the transient phosphorylation of signal transducer and activator of transcription 3 (STAT3) and the sustained activation of extracellular signal-regulated protein kinases (ERK). RNA sequencing over a time course of IL11 stimulation revealed a robust but short-lived transcriptional response that was enriched for gene set hallmarks of inflammation and characterized by the upregulation of SERPINB2, TNFRSF18, Interleukin 33 (IL33), CCL20, IL1RL1, CXCL3/5/8, ICAM1 and IL11 itself. IL33 was the most upregulated signaling factor (38-fold, p = 9.8 × 10−5), and IL1RL1, its cognate receptor, was similarly increased (18-fold, p = 1.1 × 10−34). In proteomic studies, IL11 triggered a proinflammatory secretome with the notable upregulation of IL8, IL6, MCP1, CCL20 and CXCL1/5/6, which are important chemotaxins for neutrophils, monocytes, and lymphocytes. IL11 induced IL33 expression across fibroblast types, and the inhibition of STAT3 but not of MEK/ERK prevented this. These data establish IL11 as pro-inflammatory with specific importance for priming the IL33 alarmin response in inflammatory fibroblasts across tissues.

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“…Here we define the dynamic transcriptional landscape of fibroblasts following IL11 stimulation. The time course used is of particular importance as we, and others, have struggled to detect an effect on IL11 on transcription in stromal cells in vitro at late time points (24 h) after stimulation, when its translational effects are abundant [5,6]. We documented robust and significant transcriptional effects of IL11 at 1 and 6 h post stimulation, when both STAT3 and ERK are phosphorylated across fibroblast types.…”

Section: Discussionmentioning

confidence: 77%

“…However, many of the original insights into IL11 biology were based on the use of rhIL11 in the mouse, which has unexpected effects [7,8]. This discovery underpins the realization that IL11 is profibrotic [4][5][6]9,11] whereas the earlier literature had reported it as anti-fibrotic [3,[39][40][41]. We suggest that, as it was for fibrosis, the role for IL11 in inflammation is misinterpreted.…”

Section: Discussionmentioning

confidence: 93%

“…IL11 was initially characterized as anti-inflammatory, anti-fibrotic and pro-regenerative based on experiments where recombinant human IL11 (rhIL11) was administered to mouse models of disease [3]. However, species matched IL11 was recently found to have ERK-dependent pro-fibrotic activity in fibroblasts [4][5][6][7] and it transpires that rhIL11 has unexpected activity in the mouse and inhibits endogenous murine IL11 [8]. In mammals, IL11 is now largely accepted to be pro-fibrotic [9] and is increasingly viewed as anti-regenerative [8,10,11].…”

Section: Introductionmentioning

confidence: 99%

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IL11 stimulates IL33 expression and proinflammatory fibroblast activation

Widjaja

Chothani

Sivakumar

et al. 2022

Preprint

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Interleukin 11 (IL11) is upregulated in inflammatory conditions where it is believed to have anti-inflammatory activity. However, recent studies suggest instead that IL11 may promote inflammation, via the stroma. Here, we assessed whether IL11 is pro- or anti-inflammatory in fibroblasts. Primary cultures of human kidney, lung or skin fibroblasts were stimulated with IL11 that resulted in transient STAT3 phosphorylation and bi-modal ERK activation. RNA sequencing over a time course of IL11 stimulation revealed a robust short-lived transcriptional response, which was enriched for gene set hallmarks of inflammation and characterized by upregulation of SERPINB2, TNFRSF18, IL33, CCL20, IL1RL1, CXCL3/5/8, ICAM1 and IL11 itself. IL33 was the most upregulated signaling factor (38-fold, P=9.8x10-5) and IL1RL1, its cognate receptor, was similarly increased (18-fold, P=1.1x10-34). In proteomic studies, IL11 triggered a proinflammatory secretome with notable upregulation of IL8, IL6, MCP1, CCL20 and CXCL1/5/6, which are important chemotaxins for neutrophils, monocytes and lymphocytes. IL11 induced IL33 expression across fibroblast types and inhibition of STAT3, but not MEK/ERK, prevented this. These data establish IL11 as pro-inflammatory with specific importance for priming the IL33 alarmin response in inflammatory fibroblasts.

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CD39+ Fibroblasts Enhance Myofibroblast Activation by Promoting IL-11 Secretion in Hypertrophic Scars

Cited by 19 publications

References 37 publications

Fibroblasts in Scar Formation: Biology and Clinical Translation

Fibroblasts in Scar Formation: Biology and Clinical Translation

IL11 Stimulates IL33 Expression and Proinflammatory Fibroblast Activation across Tissues

IL11 stimulates IL33 expression and proinflammatory fibroblast activation

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