TH17 cells mediate inflammation in a novel model of spontaneous experimental autoimmune lacrimal keratoconjunctivitis with neural damage

Seo, Kyoung Yul; Kitamura, Kazuya; Han, Suk Won; Kelsall, Brian L.

doi:10.1016/j.jaci.2017.07.052

Cited by 8 publications

(10 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Dry eye disease is associated with changes in corneal sensory nerve morphology and dysfunction in humans [23,24] and mice [25,26,27]. In this study, we show how the ICNs and the corneal epithelium cope with the loss of CD25.…”

Section: Introductionmentioning

confidence: 67%

Reduced Corneal Innervation in the CD25 Null Model of Sjögren Syndrome

Stepp

Pal‐Ghosh

Tadvalkar

et al. 2018

IJMS

View full text Add to dashboard Cite

Decreased corneal innervation is frequent in patients with Sjögren Syndrome (SS). To investigate the density and morphology of the intraepithelial corneal nerves (ICNs), corneal sensitivity, epithelial cell proliferation, and changes in mRNA expression of genes that are involved in autophagy and axon targeting and extension were assessed using the IL-2 receptor alpha chain (CD25 null) model of SS. ICN density and thickness in male and female wt and CD25 null corneas were assessed at 4, 6, 8, and 10/11 wk of age. Cell proliferation was assessed using ki67. Mechanical corneal sensitivity was measured. Quantitative PCR was performed to quantify expression of beclin 1, LC3, Lamp-1, Lamp-2, CXCL-1, BDNF, NTN1, DCC, Unc5b1, Efna4, Efna5, Rgma, and p21 in corneal epithelial mRNA. A significant reduction in corneal axon density and mechanical sensitivity were observed, which negatively correlate with epithelial cell proliferation. CD25 null mice have increased expression of genes regulating autophagy (beclin-1, LC3, LAMP-1, LAMP-2, CXCL1, and BDNF) and no change was observed in genes that were related to axonal targeting and extension. Decreased anatomic corneal innervation in the CD25 null SS model is accompanied by reduced corneal sensitivity, increased corneal epithelial cell proliferation, and increased expression of genes regulating phagocytosis and autophagy.

show abstract

Section: Introductionmentioning

confidence: 67%

Reduced Corneal Innervation in the CD25 Null Model of Sjögren Syndrome

Stepp

Pal‐Ghosh

Tadvalkar

et al. 2018

IJMS

View full text Add to dashboard Cite

show abstract

“…Innervation of the ocular surface and the lacrimal gland have been shown to be altered in mice with DED, as compared to naïve mice. Several murine models of DED, including DS-induced DED ( 43 , 44 ), DS combined with scopolamine to induce suppression of tear production ( 9 ), a model in which the LG is removed ( 45 ), an experimental autoimmune lacrimal keratoconjunctivitis model ( 46 ), as well as CD25 −/− and Aire −/− mice that develop Sjögren's syndrome ( 47 , 48 ) have all demonstrated significantly decreased corneal sub-basal nerve density compared with their respective control mice, irrespective of the model used. Further, in TSP −/− mice that present with aqueous deficient DED, the neuronal innervation of the LG, and in particular the parasympathetic nerves, are substantially decreased when compared to lacrimal glands of age-matched WT mice ( 49 ).…”

Section: Discussionmentioning

confidence: 99%

Effect of Dry Eye Disease on the Kinetics of Lacrimal Gland Dendritic Cells as Visualized by Intravital Multi-Photon Microscopy

et al. 2020

View full text Add to dashboard Cite

The lacrimal gland (LG) is the main source of the tear film aqueous layer and its dysfunction results in dry eye disease (DED), a chronic immune-mediated disorder of the ocular surface. The desiccating stress (DS) murine model that mimics human DED, results in LG dysfunction, immune cell infiltration, and consequently insufficient tear production. To date, the immune cell kinetics in DED are poorly understood. The purpose of this study was to develop a murine model of intravital multi-photon microscopy (IV-MPM) for the LG, and to investigate the migratory kinetics and 3D morphological properties of conventional dendritic cells (cDCs), the professional antigen presenting cells of the ocular surface, in DED. Mice were placed in a controlled environmental chamber with low humidity and increased airflow rate for 2 and 4 weeks to induce DED, while control naïve transgenic mice were housed under standard conditions. DED mice had significantly decreased tear secretion and increased fluorescein staining ( p < 0.01) compared to naïve controls. Histological analysis of the LG exhibited infiltrating mononuclear and polymorphonuclear cells ( p < 0.05), as well as increased LG swelling ( p < 0.001) in DED mice compared to controls. Immunofluorescence staining revealed increased density of cDCs in DED mice ( p < 0.001). IV-MPM of the LG demonstrated increased density of cDCs in the LGs of DED mice, compared with controls ( p < 0.001). cDCs were more spherical in DED at both time points compared to controls ( p < 0.001); however, differences in surface area were found at 2 weeks in DED compared with naïve controls ( p < 0.001). Similarly, 3D cell volume was significantly lower at 2 weeks in DED vs. the naïve controls ( p < 0.001). 3D instantaneous velocity and mean track speed were significantly higher in DED compared to naïve mice ( p < 0.001). Finally, the meandering index, an index for directionality, was significant increased at 4 weeks after DED compared with controls and 2 weeks of DED ( p < 0.001). Our IV-MPM study sheds light into the 3D morphological alterations and cDC kinetics in the LG during DED. While in naïve LGs, cDCs exhibit a more dendritic morphology and are less motile, they became more spherical with enhanced motility during DED. This study shows that IV-MPM represents a robust tool to study immune cell trafficking and kinetics in the LG, which might elucidate cellular alterations in immunological diseases, such as DED.

show abstract

“…The interaction of IL-17A with IL-17RA results in the induction of various proinflammatory cytokines (TNF, IL-1β, and IL-6, etc.) and chemokines (IL-8, CXCL1, CXCL2 and CCL20) (Mills, 2008;Seo et al, 2017). The induced cytokines influence proliferation and differentiation of epidermal keratinocytes, whereas chemokines promote the The cells were exposed to IL-17A (50 ng/mL) for the indicated periods of time, as described in the section "Materials and methods".…”

Section: Discussionmentioning

confidence: 99%

“…Their secretion to the extracellular matrix promotes the migration of activated immune cells to lesional epidermis. In turn, the accumulation of immune cells in lesional skin stabilizes there the inflammatory process (Seo et al, 2017).…”

mentioning

confidence: 99%

Rnai-Mediated Silencing of Matrix Metalloproteinase 1 in Epidermal Keratinocytes Influences the Biological Effects of Interleukin 17a

Mogulevtseva¹,

Mezentsev²,

Брускин³

2018

Vestn. VOGiS

View full text Add to dashboard Cite

Matrix metalloproteinases (MMPs) are important for the pathogenesis of psoriasis and other autoimmune disorders. In the extracellular matrix, accumulation of proinflammatory cytokines, such as interleukin 17A (IL-17A), leads to induction of several MMPs, including MMP1. MMPs change the composition and other properties of the extracellular matrix. These changes facilitate tissue remodeling and promote the development of psoriatic plaques. The aim of this study was to explore how MMP1 silencing might influence the biological effects of IL-17A on migration and proliferation of human epidermal keratinocytes and the expression of genes involved in their division and differentiation. The experiments were performed with MMP1-deficient and control epidermal keratinocytes, HaCaT-MMP1 and HaCaT-KTR, respectively. Cell proliferation and migration were assessed by comparative analysis of the growth curves and scratch assay, respectively. To quantify cell migration, representative areas of cell cultures were photographed at the indicated time points and compared to each other. Changes in gene expression were analyzed by real-time PCR. The obtained results demonstrated that MMP1 silencing in the cells treated with IL-17A resulted in downregulation of MMP9 and -12, FOSL1, CCNA2, IVL, KRT14 and -17 as well as upregulation of MMP2, CCND1 and LOR. Moreover, MMP1 silencing led to a decrease in cell proliferation and an impairment of cell migration. Thus, MMP1-deficiency in epidermal keratinocytes can be beneficial for psoriasis patients that experience an accumulation of IL-17 in lesional skin. Knocking MMP1 down could influence migration and proliferation of epidermal keratinocytes in vivo, as well as help to control the expression of MMP1, -2, -9 и -12, CCNA2, CCND1, KRT14 and -17 that are crucial for the pathogenesis of psoriasis.

show abstract

TH17 cells mediate inflammation in a novel model of spontaneous experimental autoimmune lacrimal keratoconjunctivitis with neural damage

Abstract: We describe a novel model of spontaneous EALK that supports a role for T17 cells in disease pathogenesis and that will contribute to our understanding of autoimmune lacrimal keratoconjunctivitis in many human eye diseases, including DED.

Cited by 8 publications

References 28 publications

Reduced Corneal Innervation in the CD25 Null Model of Sjögren Syndrome

Reduced Corneal Innervation in the CD25 Null Model of Sjögren Syndrome

Effect of Dry Eye Disease on the Kinetics of Lacrimal Gland Dendritic Cells as Visualized by Intravital Multi-Photon Microscopy

Rnai-Mediated Silencing of Matrix Metalloproteinase 1 in Epidermal Keratinocytes Influences the Biological Effects of Interleukin 17a

Contact Info

Product

Resources

About