MAdCAM-1 mediates retinal neuron degeneration in experimental colitis through recruiting gut-homing CD4+ T cells

Peng, Kun; Xiao, Jie; Wang, Jinxia; Song, Yaxin; Wu, Lianying; Xiu, Wenbo; Chen, Qinyuan; Chen, Yanxi; Shuai, Ping; He, Chong; Lu, Fang

doi:10.1038/s41385-020-0282-x

Cited by 13 publications

(14 citation statements)

References 46 publications

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“…Although there is general interest in the role of TNF-α and CAMs in the context of retinopathies, to our knowledge there exists only one recent study by Peng et al . demonstrating a direct function for murine Madcam1 in retinal degeneration 83 . In line with Peng et al, we demonstrated upregulation of Madcam1 in AAV-TNF-α injected eyes correlating with an invasion of T-cells.…”

Section: Discussionmentioning

confidence: 95%

“…In addition to C3, cellular adhesion molecules (CAMs), such as Icam1, Vcam1 and Madcam1 were highly upregulated in AAV-TNF-α injected eyes, strengthening the previous observation of immune cell infiltration and vasculitis in AAV-TNF-α injected eyes by histology 19 . MAdCAM-1 is induced by TNF-α in diverse endothelial cells and recruits T-cells to inflamed tissues [83][84][85] and, therefore, has recently been identified as an interesting target to treat inflammatory bowel diseases 86 . In addition to Madcam1 upregulation, we observed T-cell infiltration in our AAV-TNF-α driven uveitis-like model, in line with well-described role for T-cells in uveitis patients and uveitis rodent models 87,88 .…”

Section: Discussionmentioning

confidence: 99%

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Transcriptome analysis of AAV-induced retinopathy models expressing human VEGF, TNF-α, and IL-6 in murine eyes

Becker

Weigelt²,

Fuchs³

et al. 2022

Sci Rep

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Retinopathies are multifactorial diseases with complex pathologies that eventually lead to vision loss. Animal models facilitate the understanding of the pathophysiology and identification of novel treatment options. However, each animal model reflects only specific disease aspects and understanding of the specific molecular changes in most disease models is limited. Here, we conducted transcriptome analysis of murine ocular tissue transduced with recombinant Adeno-associated viruses (AAVs) expressing either human VEGF-A, TNF-α, or IL-6. VEGF expression led to a distinct regulation of extracellular matrix (ECM)-associated genes. In contrast, both TNF-α and IL-6 led to more comparable gene expression changes in interleukin signaling, and the complement cascade, with TNF-α-induced changes being more pronounced. Furthermore, integration of single cell RNA-Sequencing data suggested an increase of endothelial cell-specific marker genes by VEGF, while TNF-α expression increased the expression T-cell markers. Both TNF-α and IL-6 expression led to an increase in macrophage markers. Finally, transcriptomic changes in AAV-VEGF treated mice largely overlapped with gene expression changes observed in the oxygen-induced retinopathy model, especially regarding ECM components and endothelial cell-specific gene expression. Altogether, our study represents a valuable investigation of gene expression changes induced by VEGF, TNF-α, and IL-6 and will aid researchers in selecting appropriate animal models for retinopathies based on their agreement with the human pathophysiology.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Transcriptome analysis of AAV-induced retinopathy models expressing human VEGF, TNF-α, and IL-6 in murine eyes

Becker

Weigelt²,

Fuchs³

et al. 2022

Sci Rep

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“…As reported previously ( 17 ), immunofluorescence assay was performed on 6 μm-thick frozen sections of colon tissue. Slides were baked for 30 min at 37°C.…”

Section: Methodsmentioning

confidence: 99%

Carnosol Maintains Intestinal Barrier Function and Mucosal Immune Homeostasis in DSS-Induced Colitis

Zhang

Peng

et al. 2022

Front. Nutr.

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Ulcerative colitis (UC) is a chronic inflammatory disease, characterized by recurrent flares of mucosal inflammation, which is limited in the colon and rectum. Compromised epithelial barrier functions have been indicated in the initiation of UC. Carnosol (CA), a natural active ortho-diphenol diterpene compound, is one of the active ingredients in plants such as rosemary and sage. The anti-inflammatory and anti-oxidative effects of CA have been reported in several animal models, but its effect on mucosal inflammation remains elusive. We established a mouse experimental colitis model characterized by epithelial barrier destruction using dextran sulfate sodium (DSS). CA was intraperitoneally administrated. Flow cytometry was performed to determine phenotypes of intraepithelial lymphocytes and lamina propria cells. qRT-PCR was used for gene expression. ER stress in the colon was determined by immunofluorescence staining and qRT-PCR. Thapsigargin was used to induce ER stress in HCT-116 cells in vitro. We found CA significantly alleviated DSS-induced colitis in mice marked by relieved clinical symptoms and colonic pathological damage. Inflammatory cell infiltration and cytokine expression in the colon were suppressed by CA during colitis. Furthermore, CA restored epithelial barrier functions and intestinal intraepithelial lymphocyte (IEL) homeostasis in mice with DSS insults. Mechanistically, we induced endoplasmic reticulum (ER) stress in HCT-116 cells (an intestinal epithelial cell line) with thapsigargin, and CA reversed this effect. In addition, we collected inflamed mucosal biopsies from 23 patients with UC, and cultured overnight with or without CA, showing CA significantly reduced expression of ER stress signaling molecule and pro-inflammatory agents. Our data demonstrate that CA acts as an effective drug for experimental colitis and maintains proper epithelial barrier functions via suppressing epithelial ER stress, providing new evidence that CA might be a promising therapeutic candidate for UC.

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“…With regard to L-selectin as an additional interaction partner of MAdCAM-1, ontamalimab might not just be an imitation of anti-α4β7 antibody therapy, but dispose over a unique mechanism of action ( 44 , 45 ). Furthermore, expression of MAdCAM-1 in other mucosal tissues as well as in joints, eyes, skin and liver ( 46 – 48 ) make it a potential treatment option for extraintestinal manifestations of IBD and other inflammatory diseases ( 49 ).…”

Section: Targeting Cell Adhesion Molecules – Blockade On the Side Of The Effector Tissuementioning

confidence: 99%

Targeting Immune Cell Trafficking – Insights From Research Models and Implications for Future IBD Therapy

et al. 2021

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Inflammatory bowel diseases (IBDs), including Crohn’s disease (CD) and ulcerative colitis (UC) are multifactorial diseases with still unknown aetiology and an increasing prevalence and incidence worldwide. Despite plentiful therapeutic options for IBDs, the lack or loss of response in certain patients demands the development of further treatments to tackle this unmet medical need. In recent years, the success of the anti-α4β7 antibody vedolizumab highlighted the potential of targeting the homing of immune cells, which is now an important pillar of IBD therapy. Due to its complexity, leukocyte trafficking and the involved molecules offer a largely untapped resource for a plethora of potential therapeutic interventions. In this review, we aim to summarise current and future directions of specifically interfering with immune cell trafficking. We will comment on concepts of homing, retention and recirculation and particularly focus on the role of tissue-derived chemokines. Moreover, we will give an overview of the mode of action of drugs currently in use or still in the pipeline, highlighting their mechanisms and potential to reduce disease burden.

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MAdCAM-1 mediates retinal neuron degeneration in experimental colitis through recruiting gut-homing CD4+ T cells

Cited by 13 publications

References 46 publications

Transcriptome analysis of AAV-induced retinopathy models expressing human VEGF, TNF-α, and IL-6 in murine eyes

Transcriptome analysis of AAV-induced retinopathy models expressing human VEGF, TNF-α, and IL-6 in murine eyes

Carnosol Maintains Intestinal Barrier Function and Mucosal Immune Homeostasis in DSS-Induced Colitis

Targeting Immune Cell Trafficking – Insights From Research Models and Implications for Future IBD Therapy

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