Inflammatory Stress Causes N-Glycan Processing Deficiency in Ocular Autoimmune Disease

Woodward, Ashley M.; Lehoux, Sylvain; Mantelli, Flavio; Zazzo, Antonio Di; Brockhausen, Inka; Bombardieri, Stefano; Argüeso, Pablo

doi:10.1016/j.ajpath.2018.10.012

Cited by 18 publications

(10 citation statements)

References 41 publications

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“…The mean age of the control group was 62 ± 6.1 years (range, 53-71 years). Exclusion criteria for the control group included history of ocular disease or eye surgery and contact lens wear 37 . Informed consent was obtained from each recruited patient.…”

Section: Methodsmentioning

confidence: 99%

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Endoplasmic reticulum stress promotes inflammation-mediated proteolytic activity at the ocular surface

Woodward

Zazzo

Bombardieri

et al. 2020

Sci Rep

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A growing body of evidence implicates endoplasmic reticulum (eR) stress in the pathogenesis of chronic inflammatory and autoimmune disorders. Here, we demonstrate that the proinflammatory cytokine tnfα stimulates matrix metalloproteinase 9 (MMP9) at the ocular surface through a c-Fosdependent mechanism of eR stress. We found positive reactivity of the molecular chaperone Bip/ GRP78 in conjunctival epithelium of patients with ocular cicatricial pemphigoid and increased levels of BiP/GRP78, sXBP1 and GRP94 in human corneal epithelial cells treated with TNFα. pharmacological blockade of eR stress in vitro using dexamethasone or the chemical chaperones TUDCA and 4PBA attenuated MMP9 expression and secretion in the presence of TNFα. Moreover, expression analysis of genes associated with inflammation and autoimmunity identified the c-Fos proto-oncogene as a mediator of eR stress responses in epithelial cells. Substantially less tnfα-induced MMP9 expression occurred when c-Fos signaling was suppressed with a function-blocking antibody. Taken together, these results indicate that activation of ER stress contributes to promote inflammation-mediated proteolytic activity and uncovers a target for restoring tissue homeostasis in ocular autoimmune disease.

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Section: Methodsmentioning

confidence: 99%

“…All samples were normalized using GAPDH housekeeping gene expression. The comparative ΔΔC T method was used for relative quantitation of the number of transcripts 37 . No template controls were run in each assay to confirm lack of DNA contamination in the reagents used for amplification.…”

Section: Methodsmentioning

confidence: 99%

Endoplasmic reticulum stress promotes inflammation-mediated proteolytic activity at the ocular surface

Woodward

Zazzo

Bombardieri

et al. 2020

Sci Rep

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“…Interestingly, 18 of 24 cell lines are likely to express mannosyl glycans, as they were bound by a mannose-binding lectin, ConA (51). Mannosyl glycans are highly abundant in the human urogenital tract (43) and are also present on other mucosal surfaces (50, 52) that are sites of gonococcal infection. In addition to epithelial cells, human monocytes, macrophages, neutrophils, basophils, eosinophils, and dendritic and mast cells express high-mannose glycan structures (53–55).…”

Section: Discussionmentioning

confidence: 99%

Glycointeractome of Neisseria gonorrhoeae: Identification of Host Glycans Targeted by the Gonococcus To Facilitate Adherence to Cervical and Urethral Epithelial Cells

Semchenko

Everest‐Dass

Jen

et al. 2019

mBio

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Neisseria gonorrhoeae is a significant threat to global health for which a vaccine and novel treatment options are urgently needed. Glycans expressed by human cells are commonly targeted by pathogens to facilitate interactions with the host, and thus characterization of these interactions can aid identification of bacterial receptors that can be exploited as vaccine and/or drug targets. Using glycan array analysis, we identified 247 specific interactions between N. gonorrhoeae and glycans representative of those found on human cells. Interactions included those with mannosylated, fucosylated, and sialylated glycans, glycosaminoglycans (GAGs), and glycans terminating with galactose (Gal), N-acetylgalactosamine (GalNAc), and N-acetylglucosamine (GlcNAc). By investigating the kinetics of interactions with selected glycans, we demonstrate that whole-cell N. gonorrhoeae has a high affinity for mannosylated glycans (dissociation constant [KD], 0.14 to 0.59 μM), which are expressed on the surface of cervical and urethral epithelial cells. Using chromatography coupled with mass spectrometric (MS) analysis, we identified potential mannose-binding proteins in N. gonorrhoeae. Pretreatment of cells with mannose-specific lectin (concanavalin A) or free mannose competitor (α-methyl-d-mannopyranoside) substantially reduced gonococcal adherence to epithelial cells. This suggests that N. gonorrhoeae targets mannosyl glycans to facilitate adherence to host cells and that mannosides or similar compounds have the potential to be used as a novel treatment option for N. gonorrhoeae. IMPORTANCE Multidrug-resistant strains of Neisseria gonorrhoeae are emerging worldwide, and novel treatment and prevention strategies are needed. Glycans are ubiquitously expressed by all human cells and can be specifically targeted by pathogens to facilitate association with host cells. Here we identify and characterize the N. gonorrhoeae host-glycan binding profile (glycointeractome), which revealed numerous interactions, including high-affinity binding to mannosyl glycans. We identify gonococcal potential mannose-binding proteins and show that N. gonorrhoeae uses mannosyl glycans expressed on the surface of cervical and urethral epithelia to facilitate adherence. Furthermore, a mannose-binding lectin or a mannoside compound was able to reduce this adherence. By characterizing the glycointeractome of N. gonorrhoeae, we were able to elucidate a novel mechanism used by this important pathogen to interact with human cells, and this interaction could be exploited to develop novel therapeutics to treat antibiotic-resistant gonorrhea.

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“…Studies in corneal epithelium have revealed that Cephalosporium curvulum and Aspergillus oryzae use fucose-specific lectins to gain access to the host cell surface and, subsequently, promote infection and disease ( 42 ). It is worth noting here that a significant number of terminal and core fucose structures are present in the differentiated corneal epithelial glycocalyx, which could facilitate this type of interaction ( 43 ). In addition to immune cells, the corneal epithelium expresses lectins that also interact with polysaccharides on the fungal cell wall.…”

Section: The Glycocalyx In Ocular Surface Infectionmentioning

confidence: 99%

The Epithelial Cell Glycocalyx in Ocular Surface Infection

2021

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The glycocalyx is the main component of the transcellular barrier located at the interface between the ocular surface epithelia and the external environment. This barrier extends up to 500 nm from the plasma membrane and projects into the tear fluid bathing the surface of the eye. Under homeostatic conditions, defense molecules in the glycocalyx, such as transmembrane mucins, resist infection. However, many pathogenic microorganisms have evolved to exploit components of the glycocalyx in order to gain access to epithelial cells and consequently exert deleterious effects. This manuscript reviews the implications of the ocular surface epithelial glycocalyx to bacterial, viral, fungal and parasitic infection. Moreover, it presents some ongoing controversies surrounding the functional relevance of the epithelial glycocalyx to ocular infectious disease.

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Inflammatory Stress Causes N-Glycan Processing Deficiency in Ocular Autoimmune Disease

Cited by 18 publications

References 41 publications

Endoplasmic reticulum stress promotes inflammation-mediated proteolytic activity at the ocular surface

Endoplasmic reticulum stress promotes inflammation-mediated proteolytic activity at the ocular surface

Glycointeractome of Neisseria gonorrhoeae: Identification of Host Glycans Targeted by the Gonococcus To Facilitate Adherence to Cervical and Urethral Epithelial Cells

The Epithelial Cell Glycocalyx in Ocular Surface Infection

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