Stratification of Antigen-presenting Cells within the Normal Cornea

Knickelbein, Jared E.; Watkins, Simon C.; McMenamin, Paul G.; Hendricks, Robert L.

doi:10.4137/oed.s2813

Cited by 81 publications

(56 citation statements)

References 25 publications

(80 reference statements)

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“…Bone marrow derived cells are present in the normal cornea (24,25), and we showed that TLR4 expression on resident bone marrow-derived cells can mediate the host response to LPS and P. aeruginosa (17,19); however, results from the current study demonstrate that MD-2 expression on either bone marrow-derived or on non-myeloid cells is sufficient to mediate an inflammatory response, indicating that in addition to bone marrow cells, there is also a role for corneal epithelial cells in vivo.…”

Section: Discussionmentioning

confidence: 99%

Interferon-γ-induced MD-2 Protein Expression and Lipopolysaccharide (LPS) Responsiveness in Corneal Epithelial Cells Is Mediated by Janus Tyrosine Kinase-2 Activation and Direct Binding of STAT1 Protein to the MD-2 Promoter

Roy

Sun

Pearlman

2011

Journal of Biological Chemistry

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The inability of epithelial cells from the cornea and other tissues to respond to LPS is reportedly due to low expression of the TLR4 co-receptor MD-2. We generated MD-2 ؊/؊ bone marrow chimeras, and showed that MD-2 expression on nonmyeloid cells was sufficient to mediate LPS-induced corneal inflammation. As IFN-␥ is produced during Pseudomonas aeruginosa corneal infection, we examined the role of this cytokine on MD-2 expression by primary human corneal epithelial ( MD-2 is a ϳ25-kDa LPS-binding protein that forms a heterodimer with TLR4 2 (1-3). The crystal structure of the TLR4-MD-2 complex shows that when five of the six acyl chains of lipid A bind MD-2 and one chain binds to TLR4, it undergoes a structural change that facilitates dimerization and cell activation (4). The canonical signaling pathway involves recruitment of MyD88 and Mal/TIRAP adaptor molecules to the TIR domain of TLR4, which initiates the canonical signaling pathway leading to NFB translocation to the nucleus and production of proinflammatory and chemotactic cytokines (5, 6). The TLR4-MD-2 complex is also internalized (7), leading to recruitment of adaptor molecules TRIF-related adaptor molecule (TRAM) and TRIF and to nuclear translocation of NFB and IRF3 and production of type I IFNs (5, 6). In macrophages and dendritic cells, MD-2 is expressed constitutively, thereby mediating LPS responsiveness (1,8). In contrast, epithelial cells do not constitutively express MD-2 and do not respond to LPS unless MD-2 is provided exogenously (9 -11). MD-2 expression in intestinal, airway, oral, and conjunctival epithelial cells is induced by , although neither the source of IFN-␥ or the mechanism of induction has been fully elucidated.In the current study we examine the role of MD-2 and expression of IFN-␥ in the context of corneal infection and inflammation and determine the molecular basis for LPS hyporesponsiveness and MD-2 expression in the presence of IFN-␥ in human corneal epithelial cells.

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Section: Discussionmentioning

confidence: 99%

Interferon-γ-induced MD-2 Protein Expression and Lipopolysaccharide (LPS) Responsiveness in Corneal Epithelial Cells Is Mediated by Janus Tyrosine Kinase-2 Activation and Direct Binding of STAT1 Protein to the MD-2 Promoter

Roy

Sun

Pearlman

2011

Journal of Biological Chemistry

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“…10 This difference in rejection rate can be explained, at least in part, by differential immunological responses between BALB/c and host C57BL/6 mouse strains. 11 MPS and other innate immune cells (some expressing MHCclass II antigens) are present in the corneal epithelial layer and stroma, [12][13][14][15][16] especially in the peripheral cornea (limbus). 17 Following the induction of inflammation, MPS are activated and the expression of MHC-class II, as well as co-stimulatory molecules, such as CD80 (B7.1), CD86 (B7.2), and CD40, is increased.…”

mentioning

confidence: 99%

The Maintenance of Lymphatic Vessels in the Cornea Is Dependent on the Presence of Macrophages

Maruyama

Nakazawa

Cursiefen

et al. 2012

Invest. Ophthalmol. Vis. Sci.

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“…24 -26 DCs are another cell population located at the basal layer of the corneal epithelium. 12,[27][28][29][30] Unlike PMNs and ␥␦T cells, which are usually not found in the cornea, 25,31 DCs are present and embedded in the epithelia of many mucosal surfaces. 1,5 Thus, both epithelial cells and intraepithelial DCs are in the front line facing external environments and can sense danger signals, including tissue injury and infection.…”

mentioning

confidence: 99%

Dendritic Cell–Epithelium Interplay Is a Determinant Factor for Corneal Epithelial Wound Repair

Gao

Yin

Yoon

et al. 2011

The American Journal of Pathology

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The functions of intraepithelial dendritic cells (DCs) are critical for mucosal innate and adaptive immunity, but little is known about the role of tissue-specific DCs in epithelial homeostasis and tissue repair. By using the epithelial debridement wound model and CD11c-diphtheria toxin receptor mice that express a CD11c promoter-driven diphtheria toxin receptor, we showed that DCs migrate along with the epithelial sheet to cover the wound and that local depletion of DCs resulted in a significant delay in epithelial wound closure. In response to wounding, migratory epithelia produce CXCL10, thymic stromal lymphopoietin, and IL-1␤ and its antagonist soluble IL-1 receptor antagonist (sIL-1Ra); depletion of corneal DCs reversed their elevated expressions to a different extent, suggesting a DC-mediated positive feedback loop in epithelial gene expression. Furthermore, both CXCL10 and thymic stromal lymphopoietin were localized in migratory epithelia, suggesting that epithelial cells play a key role in DC infiltration and activation in injured corneas. On the other hand, DC depletion resulted in suppressed epithelial AKT activation, increased cell apoptosis, and decreased polymorphonuclear leukocyte infiltration in the healing cornea. These results indicate that DCs and epithelium form a functional entity at mucosal surfaces for maintaining corneal homeostasis and for tissue repair.

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Stratification of Antigen-presenting Cells within the Normal Cornea

Cited by 81 publications

References 25 publications

Interferon-γ-induced MD-2 Protein Expression and Lipopolysaccharide (LPS) Responsiveness in Corneal Epithelial Cells Is Mediated by Janus Tyrosine Kinase-2 Activation and Direct Binding of STAT1 Protein to the MD-2 Promoter

Interferon-γ-induced MD-2 Protein Expression and Lipopolysaccharide (LPS) Responsiveness in Corneal Epithelial Cells Is Mediated by Janus Tyrosine Kinase-2 Activation and Direct Binding of STAT1 Protein to the MD-2 Promoter

The Maintenance of Lymphatic Vessels in the Cornea Is Dependent on the Presence of Macrophages

Dendritic Cell–Epithelium Interplay Is a Determinant Factor for Corneal Epithelial Wound Repair

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