γδ Intraepithelial Lymphocytes Facilitate Pathological Epithelial Cell Shedding Via CD103-Mediated Granzyme Release

Hu, Madeleine D.; Golovchenko, N.; Burns, Grace; Nair, Prema M.; Kelly, Thomas J.; Agos, Jonathan; Irani, Mudar Zand; Soh, Wai Sinn; Zeglinski, Matthew R.; Lemenze, Alexander; Bonder, Edward M.; Sandrock, Inga; Prinz, Immo; Granville, David J.; Keely, Simon; Watson, Alastair; Edelblum, Karen L.

doi:10.1053/j.gastro.2021.11.028

Cited by 34 publications

(38 citation statements)

References 54 publications

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“…Evidence for targeting extracellular GrB has been validated via models of various cardiovascular, dermatological, neuroinflammatory, gastroenterological and respiratory pathologies utilizing genetic knockouts, biologics and/or small molecules (Aneurysm - ( Chamberlain et al, 2010 ; Ang et al, 2011 ); Atherosclerosis - (Paul R. Hiebert PR. et al, 2013 ); Cardiac fibrosis - ( Shen et al, 2016 ); Cerebral ischemia - ( Aslam and Yuan, 2020 ); Vascular leakage -( Hendel and Granville, 2013 ; Hendel et al, 2014 ); Chronic wound healing - (P. R. Hiebert P. R. et al, 2013 ; Hsu et al, 2014 ; Turner et al, 2021a ); Skin aging - ( Hiebert et al, 2011 ; Parkinson et al, 2015 ); Scarring - ( Shen et al, 2018 ); Autoimmune blistering - ( Russo et al, 2018 ; Hiroyasu et al, 2021 ); Dermatitis - ( Turner et al, 2021 ); Multiple sclerosis - ( Haile et al, 2015 ); Crohn’s disease - ( Hu et al, 2022 ); Asthma - ( Qian et al, 2020 )). From these studies, pharmacological inhibition of extracellular GrB appears to be the most viable avenue of therapy, with the biologic Serpina3n and the small molecule VTI-1002 both exhibiting therapeutic efficacy.…”

Section: Age-related Diseases In the Eyementioning

confidence: 99%

Potential role of extracellular granzyme B in wet age-related macular degeneration and fuchs endothelial corneal dystrophy

Dubchak

Obasanmi²,

Zeglinski³

et al. 2022

Front. Pharmacol.

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Age-related ocular diseases are the leading cause of blindness in developed countries and constitute a sizable socioeconomic burden worldwide. Age-related macular degeneration (AMD) and Fuchs endothelial corneal dystrophy (FECD) are some of the most common age-related diseases of the retina and cornea, respectively. AMD is characterized by a breakdown of the retinal pigment epithelial monolayer, which maintains retinal homeostasis, leading to retinal degeneration, while FECD is characterized by degeneration of the corneal endothelial monolayer, which maintains corneal hydration status, leading to corneal edema. Both AMD and FECD pathogenesis are characterized by disorganized local extracellular matrix (ECM) and toxic protein deposits, with both processes linked to aberrant protease activity. Granzyme B (GrB) is a serine protease traditionally known for immune-mediated initiation of apoptosis; however, it is now recognized that GrB is expressed by a variety of immune and non-immune cells and aberrant extracellular localization of GrB substantially contributes to various age-related pathologies through dysregulated cleavage of ECM, tight junction, and adherens junction proteins. Despite growing recognition of GrB involvement in multiple age-related pathologies, its role in AMD and FECD remains poorly understood. This review summarizes the pathophysiology of, and similarities between AMD and FECD, outlines the current knowledge of the role of GrB in AMD and FECD, as well as hypothesizes putative contributions of GrB to AMD and FECD pathogenesis and highlights the therapeutic potential of pharmacologically inhibiting GrB as an adjunctive treatment for AMD and FECD.

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Section: Age-related Diseases In the Eyementioning

confidence: 99%

Potential role of extracellular granzyme B in wet age-related macular degeneration and fuchs endothelial corneal dystrophy

Dubchak

Obasanmi²,

Zeglinski³

et al. 2022

Front. Pharmacol.

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“…Observing molecular and/or cellular biology in vivo has changed how we view many aspects of intestinal biology, including the reorganization of epithelial tight junction proteins (Marchiando et al, 2011;Marchiando et al, 2010;Watson et al, 2005), immune/epithelial interactions (McDole et al, 2012;Rescigno et al, 2001;Sumida et al, 2017;Wang et al, 2014), and the regulation of lymphocyte migration within the gut (Hoytema van Konijnenburg et al, 2017;Sujino et al, 2016;Sumida & Cyster, 2018). Whereas IELs were first observed interacting with apoptotic intestinal epithelial cells using electron microscopy in the late 1990s (Shibahara et al, 1995), we have recently shown that γδ IELs make extended contact with apoptotic enterocytes to facilitate their extrusion into the intestinal lumen (Hu et al, 2022). Thus, visualization of complex cellular dynamics within a tissue is advantageous in identifying novel functions or cellular responses in health and disease.…”

Section: Commentary Background Informationmentioning

confidence: 99%

“…Identifying a cell of interest using a reporter mouse strain is the most efficient strategy for labeling and tracking cell migration during intravital imaging (Basic Protocol 2); we use TcrdEGFP and TcrdGDL mice to track γδ IELs Hu et al, 2022). However, various immune cells, including CD8α + IELs, can be labeled with fluorophoreconjugated primary antibodies prior to imaging to identify specific cell populations of interest (Sumida & Cyster, 2018;Sumida et al, 2017;Wang et al, 2014).…”

Section: Antibody Labeling Of Cell Surface Markersmentioning

confidence: 99%

Intravital Microscopy to Visualize Murine Small Intestinal Intraepithelial Lymphocyte Migration

Fischer

Edelblum

2022

Current Protocols

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Intraepithelial lymphocytes (IELs) are critical sentinels involved in host defense and maintenance of the intestinal mucosal barrier. IELs expressing the γδ T‐cell receptor provide continuous surveillance of the villous epithelium by migrating along the basement membrane and into the lateral intercellular space between adjacent enterocytes. Intravital imaging has furthered our understanding of the molecular mechanisms by which IELs navigate the epithelial compartment and interact with neighboring enterocytes at steady state and in response to infectious or inflammatory stimuli. Further, evaluating IEL migratory behavior can provide additional insight into the nature and extent of cellular interactions within the intestinal mucosa. Three protocols describe methodology to visualize small intestinal IEL motility in real time using fluorescent reporter–transgenic mice and/or fluorophore‐conjugated primary antibodies and spinning‐disk confocal microscopy. Using Imaris image analysis software, a fourth protocol provides a framework to analyze IEL migration and quantify lymphocyte/epithelial interactions. Together, these protocols for intravital imaging and subsequent analyses provide the basis for elucidating the spatiotemporal dynamics of mucosal immune cells and interactions with neighboring enterocytes under physiological or pathophysiological conditions. © 2022 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Mouse preparation and laparotomy Support Protocol: Antibody labeling of cell surface markers Basic Protocol 2: Image acquisition by spinning‐disk confocal microscopy Basic Protocol 3: 4D analysis of images

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“…The IELs are tissue‐resident T cells that broadly can be divided in a large group expressing the αβ T cell receptor, and a smaller group mainly expressing the γδ T cell receptor [ 8 , 9 , 11 , 12 , 13 ]. The γδ T cells are enriched in mucosal tissues where they patrol the epithelium, protect against pathogens, and promote epithelial repair [ 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 ]. Their role in IBD is unclear.…”

Section: Introductionmentioning

confidence: 99%

Deep learning‐based image analysis reveals significant differences in the number and distribution of mucosal CD3 and γδ T cells between Crohn's disease and ulcerative colitis

Røyset

Pettersen

et al. 2022

The Journal of Pathology CR

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Colon mucosae of ulcerative colitis (UC) and Crohn's disease (CD) display differences in the number and distribution of immune cells that are difficult to assess by eye. Deep learning‐based analysis on whole slide images (WSIs) allows extraction of complex quantitative data that can be used to uncover different inflammatory patterns. We aimed to explore the distribution of CD3 and γδ T cells in colon mucosal compartments in histologically inactive and active inflammatory bowel disease. By deep learning‐based segmentation and cell detection on WSIs from a well‐defined cohort of CD (n = 37), UC (n = 58), and healthy controls (HCs, n = 33), we quantified CD3 and γδ T cells within and beneath the epithelium and in lamina propria in proximal and distal colon mucosa, defined by the Nancy histological index. We found that inactive CD had significantly fewer intraepithelial γδ T cells than inactive UC, but higher total number of CD3 cells in all compartments than UC and HCs. Disease activity was associated with a massive loss of intraepithelial γδ T cells in UC, but not in CD. The total intraepithelial number of CD3 cells remained constant regardless of disease activity in both CD and UC. There were more mucosal CD3 and γδ T cells in proximal versus distal colon. Oral corticosteroids had an impact on γδ T cell numbers, while age, gender, and disease duration did not. Relative abundance of γδ T cells in mucosa and blood did not correlate. This study reveals significant differences in the total number of CD3 and γδ T cells in particularly the epithelial area between CD, UC, and HCs, and demonstrates useful application of deep segmentation to quantify cells in mucosal compartments.

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γδ Intraepithelial Lymphocytes Facilitate Pathological Epithelial Cell Shedding Via CD103-Mediated Granzyme Release

Cited by 34 publications

References 54 publications

Potential role of extracellular granzyme B in wet age-related macular degeneration and fuchs endothelial corneal dystrophy

Potential role of extracellular granzyme B in wet age-related macular degeneration and fuchs endothelial corneal dystrophy

Intravital Microscopy to Visualize Murine Small Intestinal Intraepithelial Lymphocyte Migration

Deep learning‐based image analysis reveals significant differences in the number and distribution of mucosal CD3 and γδ T cells between Crohn's disease and ulcerative colitis

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