A20 is a master switch of IL-33 signaling in macrophages and determines IL-33–induced lung immunity

Holgado, Aurora; Liu, Zhuangzhuang; Aidarova, Aigerim; Mueller, Christina; Haegman, Mira; Driege, Yasmine; Kreike, Marja; Scott, Charlotte; Afonina, Inna S.; Beyaert, Rudi

doi:10.1016/j.jaci.2023.02.026

Cited by 10 publications

(9 citation statements)

References 62 publications

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“…In an ovalbumin (OVA)-induced allergic-asthma model in mice, it was shown that overexpression of A20 by adenovirus attenuates the recruitment of airway inflammatory cells and peribronchiolar inflammation and suppresses the production of various cytokines in bronchial secretions [ 77 ]. IL-33, known as a key mediator in the pathogenesis of allergic diseases such as asthma or atopic dermatitis, causes increased STAT1 signaling and IFN-γ expression in mice with A20-deficient macrophages, as already mentioned [ 40 ].…”

Section: Reviewmentioning

confidence: 79%

“…A20 has shown to influence several cell types of the innate and adaptive immune system. In macrophages, A20 inhibits Interleukin-33-induced signal transducer and activator of transcription 1 (STAT1) signaling, leading to reduced interferon-γ (IFN-γ) production and increased anti-inflammatory IL-4-mediated STAT6 signaling [ 40 ]. In addition, it suppresses NLRP3-mediated M1 polarization of macrophages, shifting the balance more towards the anti-inflammatory M2 subtype [ 41 , 42 ].…”

Section: Reviewmentioning

confidence: 99%

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A20 in Kidney Transplantation and Autoimmunity

Kommer,

Meineck,

Classen

et al. 2024

IJMS

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A20, the central inhibitor of NFκB, has multiple anti-inflammatory properties, making it an interesting target in kidney autoimmune disease and transplant biology. It has been shown to be able to inhibit inflammatory functions in macrophages, dendritic cells, T cells, and B cells in various ways, leading to less tissue damage and better graft outcomes. In this review, we will discuss the current literature regarding A20 in kidney transplantation and autoimmunity. Future investigations on animal models and in existing immunosuppressive therapies are needed to establish A20 as a therapeutic target in kidney transplantation and autoimmunity. Cell-based therapies, modified viruses or RNA-based therapies could provide a way for A20 to be utilized as a promising mediator of inflammation and tissue damage.

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Section: Reviewmentioning

confidence: 79%

Section: Reviewmentioning

confidence: 99%

A20 in Kidney Transplantation and Autoimmunity

Kommer,

Meineck,

Classen

et al. 2024

IJMS

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“…Recently, A20 was also shown to control type-2 immunity in the lung. Deletion of A20 in macrophages was reported to suppress IL33–dependent expansion of lung ILC2s, type 2 cytokine production, and eosinophilia 39 . These data are in line with our findings supporting an impaired intestinal type-2 immune response upon A20 deletion in colonic macrophages.…”

Section: Resultsmentioning

confidence: 99%

Myeloid A20 is critical for type-2 immune mediated helminth resistance

Petta,

Thorp,

Ciers

et al. 2023

Preprint

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Protective immunity against intestinal helminths requires induction of robust Type-2 immunity orchestrated by various cellular and soluble effectors which promote goblet cell hyperplasia, mucus production, epithelial proliferation and smooth muscle contractions to expel worms and reestablish immune homeostasis. Conversely, defects in type-2 immunity result in ineffective helminth clearance, persistent infection and chronic inflammation. We identify A20 as an essential myeloid factor for the induction of type-2 immune responses against the intestinal parasite Trichuris muris. Myeloid cell-specific loss of A20 in mice (A20myel-KO) results in chronic Trichuris muris infection and intestinal inflammation. Myeloid A20 deficient mice are not able to induce anti-helmith type-2 immune responses while instead mount detrimental Th1/Th17 polarized immune responses. Antibody-mediated neutralization of the type-1 cytokines IFNγ, IL18 and IL12 prevents Th1/Th17 polarization and reestablishes Type-2 mediated protective immunity against Trichuris muris in A20myel-KO mice. In contrast, the strong Th1/Th17 biased immunity in A20myel-KO mice offers protection against Salmonella infection. We hereby identify A20 as an essential myeloid factor to initiate approriate adaptive immunity in response to infection, and to induce a balanced type-2 immune response against the intestinal parasite Trichuris muris.

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“…Furthermore, IL-33 also activates additional subsets, such as Th2 cells, basophils, eosinophils, and macrophages [ 11 , 53 , 55 , 56 ]. Recent studies have shown that IL-33 directly affected differentiation of macrophage subset, which mediated the resolution of inflammation [ 57 ], tissue repair[ 58 ]or drug-resistant properties in cancer [ 59 ].In early pregnancy, decidual macrophages (dMφs) from recurrent spontaneous abortion (RSA) patients presented a M1 phenotype with high secretion of IL-33 and decreased expression of ST2. IL-33/ST2 axis modulates the polarization and efferocytosis of decidual macrophages (dMφs) [ 60 ], lead to pregnancy failure [ 61 ].Macrophage-derived IL-33 also upregulates SLC7A11 in ectopic endometrial stromal cells and protects against ferroptosis in eESC, accelerating the progression of endometriosis [ 62 ].…”

Section: Discussionmentioning

confidence: 99%

The IL-33-ST2 axis plays a vital role in endometriosis via promoting epithelial–mesenchymal transition by phosphorylating β-catenin

Ruan,

Tian,

et al. 2024

Cell Commun Signal

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Objectives Interleukin 33 (IL-33) is a crucial inflammatory factor that functions as an alarm signal in endometriosis (EMs). Epithelial-mesenchymal transition (EMT), a process related to inflammatory signals, intracellular reactive oxygen species (ROS) production, and lipid peroxidation, have been proposed as potential mechanisms that contribute to the development and progression of EMs. IL-33 is highly upregulated in the ectopic milieu. Moreover, ectopic endometrial cells constitutively express interleukin-33 receptor ST2 (IL-33R). However, the role of IL-33/ST2 in the EMT of EMs remains largely unknown. In this study, we aimed to mechanistically determine the role of IL-33/ST2 in EMs-associated fibrosis. Materials and methods We established a non-lethal oxidative stress model to explore the conditions that trigger IL-33 induction. We performed α-smooth muscle actin (α-SMA) protein detection, cell counting kit-8 (CCK-8) assays, and scratch assays to analyze the impact of IL-33 on primary endometrial stromal cells (ESCs) proliferation and invasion. Clinical samples from patients with or without EMs were subjected to immunohistochemical (IHC) and and immunofluorescence(IF) staining to assess the clinical relevance of IL-33 receptor ST2 and EMT-related proteins. Furthermore, we used the ectopic human endometrial epithelial cell line 12Z and normal human epithelial cell line EEC to evaluate the effects of IL-33 on Wnt/β-catenin signaling. The effect of IL-33 on EMT-associated fibrosis was validated in vivo by intraperitoneal injections of IL-33 and antiST2. Results We observed that ectopic milieu, characterized by ROS, TGF-β1, and high level of estrogen, triggers the secretion of IL-33 from ectopic ESCs. Ectopic endometrial lesions exhibited higher level of fibrotic characteristics and ST2 expression than that in the normal endometrium. Exogenous recombinant human (rhIL-33) enhanced ESC migration and survival. Similarly, 12Z cells displayed a higher degree of EMT characteristics with elevated expression of CCN4 and Fra-1, downstream target genes of the WNT/β-catenin pathway, than that observed in EECs. Conversely, blocking IL-33 with neutralizing antibodies, knocking down ST2 or β-catenin with siRNA, and β-catenin dephosphorylation abolished its effects on EMT promotion. In vivo validation demonstrated that IL-33 significantly promotes EMs-related fibrosis through the activation of Wnt/β-catenin signaling. Conclusion Our data strongly support the vital role of the IL-33/ST2 pathway in EMs-associated fibrosis and emphasize the importance of the EMT in the pathophysiology of fibrosis. Targeting the IL-33/ST2/Wnt/β-catenin axis may hold promise as a feasible therapeutic approach for controlling fibrosis in EMs.

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A20 is a master switch of IL-33 signaling in macrophages and determines IL-33–induced lung immunity

Cited by 10 publications

References 62 publications

A20 in Kidney Transplantation and Autoimmunity

A20 in Kidney Transplantation and Autoimmunity

Myeloid A20 is critical for type-2 immune mediated helminth resistance

The IL-33-ST2 axis plays a vital role in endometriosis via promoting epithelial–mesenchymal transition by phosphorylating β-catenin

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