IL-33 improves wound healing through enhanced M2 macrophage polarization in diabetic mice

He, Rong-guo; Yin, Hui; Yuan, Baohong; Liu, Tao; Luo, Li; Huang, Peijun; Dai, Liangcheng; Zeng, Kang

doi:10.1016/j.molimm.2017.06.249

Cited by 96 publications

(71 citation statements)

References 40 publications

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“…This essential requirement for IL‐13 to enable IL‐33‐induced polarization is due to the induction of ST2 by IL‐13 . Thus, it is likely that the induction of IL‐13 in recruited ILC2s precedes and is essential for the subsequent enhanced M2 polarization by IL‐33 . IL‐33‐induced ILC2s are also an important source of IL‐13 in liver fibrosis via the ST2‐dependent signaling pathway , which would be consistent with the reduction in IL‐13 expression in ST2‐deficient mice in the BLM model of pulmonary fibrosis, thus impacting negatively on M2 polarization as noted.…”

Section: Discussionsupporting

confidence: 60%

An ST2‐dependent role of bone marrow‐derived group 2 innate lymphoid cells in pulmonary fibrosis

Zhao

Santos

et al. 2018

The Journal of Pathology

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Recent evidence supports that bone marrow (BM)-derived hematopoietic progenitor cells play an important role in lung injury and fibrosis. While these cells give rise to multiple cell types, the ST2 (Il1rl1)-expressing group 2 innate lymphoid cells (ILC2s) derived from BM progenitors have been implicated in tissue repair and remodeling, including in lung fibrosis. To further investigate the precise role of BM-derived ILC2s in the pathogenesis of fibrotic lung disease, their importance in the bleomycin-induced lung fibrosis model was evaluated by analyzing the effects of selective ST2 deficiency in the BM compartment. The results showed that while ST2-sufficient control mice exhibited activation of lung IL-33/ST2 signaling, ILC2 recruitment, IL-13 induction, and fibrosis, these responses were significantly diminished in ST2-deficient-BM chimera mice, with selective loss of ST2 expression only in the BM. This diminished response to bleomycin was similar to that seen in ST2 global knockout mice, suggesting the predominant importance of ST2 from the BM compartment. In wild-type mice, ILC2 recruitment to the lung was accompanied by a concomitant decrease in ST2 BM cells. ST2-deficient BM cells were unresponsive to IL-33-induced ILC2 maturation. Finally, lineage-negative wild-type, but not ST2-deficient BM cells from bleomycin-treated mice stimulated lung fibroblast type I collagen expression, which was associated with elevated TGFβ expression in the BM cells. Taken together, these findings suggested that the BM-derived ILC2s were recruited to fibrotic lung through the IL-33/ST2 pathway, and contributed to fibroblast activation to promote lung fibrosis. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Section: Discussionsupporting

confidence: 60%

An ST2‐dependent role of bone marrow‐derived group 2 innate lymphoid cells in pulmonary fibrosis

Zhao

Santos

et al. 2018

The Journal of Pathology

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“…However, in unhealed wounds, such as diabetic ulcers, macrophages are chronically activated and restrained to the M1 phenotype, heavily contributing to the chronic inflammatory microenvironment observed in these wounds. Moreover, such prolonged inflammation delays the process of tissue regeneration, including re-epithelialization, granulation tissue formation, and vascularization (Boniakowski et al, 2017;He et al, 2017;Maruyama et al, 2007;Okizaki et al, 2015). Enhancing macrophage polarization toward the M2 phenotype may help to promote cellular proliferation and angiogenesis and to accelerate diabetic wound closure (He et al, 2017;Leal et al, 2015;Okizaki et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Cutaneous Wound Healing in Diabetic Mice Is Improved by Topical Mineralocorticoid Receptor Blockade

Nguyen

Farman

Palacios

et al. 2020

Journal of Investigative Dermatology

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Skin ulcers resulting from impaired wound healing are a serious complication of diabetes. Unresolved inflammation, associated with the dysregulation of both the phenotype and function of macrophages, is involved in the poor healing of diabetic wounds. Here, we report that topical pharmacological inhibition of the mineralocorticoid receptor (MR) by canrenoate or MR small interfering RNA can resolve inflammation to improve delayed skin wound healing in diabetic mouse models; importantly, wounds from normal mice are unaffected. The beneficial effect of canrenoate is associated with an increased ratio of anti-inflammatory M2 macrophages to proinflammatory M1 macrophages in diabetic wounds. Furthermore, we show that MR blockade leads to downregulation of the MR target, LCN2, which may facilitate macrophage polarization toward the M2 phenotype and improve impaired angiogenesis in diabetic wounds. Indeed, diabetic LCN2-deficient mice showed improved wound healing associated with macrophage M2 polarization and angiogenesis. In addition, recombinant LCN2 protein prevented IL-4einduced macrophage switch from M1 to M2 phenotype. In conclusion, topical MR blockade accelerates skin wound healing in diabetic mice via LCN2 reduction, M2 macrophage polarization, prevention of inflammation, and induction of angiogenesis.

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“…Although IL-33 is pathogenic in AD models, a tissue-reparative function of IL-33 was demonstrated in woundhealing models. IL-33 treatment improves wound healing in diabetic mice by enhancing M2 macrophage polarization [41] or the expansion of ILC2s [42].…”

Section: Skin Diseasesmentioning

confidence: 99%

Therapeutic Strategies for Targeting IL-33/ST2 Signalling for the Treatment of Inflammatory Diseases

Chen

Tsai

Yang

et al. 2018

Cell Physiol Biochem

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Interleukin (IL)-33, a member of the IL-1 family of cytokines, is involved in innate and adaptive immune responses via interaction with its receptor, ST2. Activation of ST2 signalling by IL-33 triggers pleiotropic immune functions in multiple ST2-expressing immune cells, including macrophages, neutrophils, eosinophils, basophils, mast cells, type 2 helper T cells, regulatory T cells, and group 2 innate lymphoid cells. IL-33-mediated effector functions contribute to the tissue inflammatory and reparative responses in various organs including lung, skin, kidney, central nerve system, cardiovascular system, and gastrointestinal system. Endogenous IL-33/ ST2 signaling exhibits diverse immune regulatory functions during progression of different diseases. IL-33 likely functions as a disease sensitizer and plays pathological roles in inflamed tissues in allergic disorders that involve hyperreactive immune responses in the context of skin and pulmonary allergy. However, IL-33 also mediates tissue-protective functions during the recovery phase following tissue injury in the central nerve system and gastrointestinal system. Modulation of the IL-33/ST2 axis, therefore, represents a promising strategy for treating immune disorders that involve dysregulation of the cytokine signalling. In the past two decades, therapeutic strategies blocking IL-33/ST2 have been extensively studied for the treatment of diseases in animal models. In this review, the current progress on the development of therapeutic biologics for targeting IL-33/ST2 signalling in inflammatory diseases is summarized.

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IL-33 improves wound healing through enhanced M2 macrophage polarization in diabetic mice

Cited by 96 publications

References 40 publications

An ST2‐dependent role of bone marrow‐derived group 2 innate lymphoid cells in pulmonary fibrosis

An ST2‐dependent role of bone marrow‐derived group 2 innate lymphoid cells in pulmonary fibrosis

Cutaneous Wound Healing in Diabetic Mice Is Improved by Topical Mineralocorticoid Receptor Blockade

Therapeutic Strategies for Targeting IL-33/ST2 Signalling for the Treatment of Inflammatory Diseases

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