NOD and NOR mice exhibit comparable development of lacrimal gland secretory dysfunction but NOD mice have more severe autoimmune dacryoadenitis

Ju, Yaping; Janga, Srikanth Reddy; Klinngam, Wannita; MacKay, J. Andrew; Hawley, Dillon; Zoukhri, Driss; Edman, Maria C.; Hamm‐Alvarez, Sarah F.

doi:10.1016/j.exer.2018.09.002

Cited by 17 publications

(21 citation statements)

References 58 publications

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“…cohort, although not necessarily sicker. As we have noted 43,44,47 , disease development is variable across cohorts; lymphocytic infiltration and tear CTSS activity values were actually higher in these 16-week cohorts than the 20-week cohorts, although older mice may manifest other indications of disease. It is possible that the prolonged exposure of ocular surface and draining lymph nodes to CTSS inhibition is required to obtain the additional suppression of proinflammatory cytokines and other effectors of disease that did not occur with i.p.…”

Section: Discussionmentioning

confidence: 58%

Inhibition of Cathepsin S Reduces Lacrimal Gland Inflammation and Increases Tear Flow in a Mouse Model of Sjögren’s Syndrome

Klinngam

Janga

Lee

et al. 2019

Sci Rep

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Cathepsin S (CTSS) is highly increased in Sjögren’s syndrome (SS) patients tears and in tears and lacrimal glands (LG) of male non-obese diabetic (NOD) mice, a murine model of SS. To explore CTSS’s utility as a therapeutic target for mitigating ocular manifestations of SS in sites where CTSS is increased in disease, the tears and the LG (systemically), the peptide-based inhibitor, Z-FL-COCHO (Z-FL), was administered to 14–15 week male NOD mice. Systemic intraperitoneal (i.p.) injection for 2 weeks significantly reduced CTSS activity in tears, LG and spleen, significantly reduced total lymphocytic infiltration into LG, reduced CD3+ and CD68+ cell abundance within lymphocytic infiltrates, and significantly increased stimulated tear secretion. Topical administration of Z-FL to a different cohort of 14–15 week male NOD mice for 6 weeks significantly reduced only tear CTSS while not affecting LG and spleen CTSS and attenuated the disease-progression related reduction of basal tear secretion, while not significantly impacting lymphocytic infiltration of the LG. These findings suggest that CTSS inhibitors administered either topically or systemically can mitigate aspects of the ocular manifestations of SS.

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Section: Discussionmentioning

confidence: 58%

Inhibition of Cathepsin S Reduces Lacrimal Gland Inflammation and Increases Tear Flow in a Mouse Model of Sjögren’s Syndrome

Klinngam

Janga

Lee

et al. 2019

Sci Rep

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“…Each sample was split in half to assay both CTSS activity and CX3CL1 content (below). Activity was measured with the CTSS activity fluorometric assay kit according to the manufacturer's instructions 7 . Fluorescence was measured using 400/505 nm excitation/emission filters in a SpectraMax iD3 (Molecular Devices, San Jose, CA).…”

Section: Analysis Of Gene Expression In Cells and Tissues Rna From Mmentioning

confidence: 99%

Cathepsin S activation contributes to elevated CX3CL1 (fractalkine) levels in tears of a Sjögren’s syndrome murine model

Guo

Janga

et al. 2020

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Autoimmune dacryoadenitis and altered lacrimal gland (LG) secretion are features of Sjögren's syndrome (SS). Activity of cathepsin S (CTSS), a cysteine protease, is significantly and specifically increased in SS patient tears. The soluble chemokine, CX3CL1 (fractalkine), is cleaved from membranebound CX3CL1 by proteases including CTSS. We show that CX3CL1 is significantly elevated by 2.5fold in tears (p = 0.0116) and 1.4-fold in LG acinar cells (LGAC)(p = 0.0026) from male NOD mice, a model of autoimmune dacryoadenitis in SS, relative to BALB/c controls. Primary mouse LGAC and human corneal epithelial cells (HCE-T cells) exposed to interferon-gamma, a cytokine elevated in SS, showed up to 9.6-fold (p ≤ 0.0001) and 25-fold (p ≤ 0.0001) increases in CX3CL1 gene expression, and 1.9-fold (p = 0.0005) and 196-fold (p ≤ 0.0001) increases in CX3CL1 protein expression, respectively. Moreover, exposure of HCE-T cells to recombinant human CTSS at activity equivalent to that in SS patient tears increased cellular CX3CL1 gene and protein expression by 2.8-fold (p = 0.0021) and 5.1fold (p ≤ 0.0001), while increasing CX3CL1 in culture medium by 5.8-fold (p ≤ 0.0001). Flow cytometry demonstrated a 4.5-fold increase in CX3CR1-expressing immune cells (p ≤ 0.0001), including increased T-cells and macrophages, in LG from NOD mice relative to BALB/c. CTSS-mediated induction/cleavage of CX3CL1 may contribute to ocular surface and LG inflammation in SS. Sjögren's syndrome (SS) is a systemic autoimmune disease associated with lymphocytic infiltration of lacrimal glands (LG) and salivary glands (SG), associated with dacryoadenitis and sialoadenitis, respectively 1. SS patients develop associated complications including reduced tear and saliva production, blurred vision, corneal damage, dental cavities and oral thrush 1. Inflammation in the LG promotes release of pro-inflammatory cytokines to the ocular surface, which can further compromise tear secretion by disruption of corneal sensory and efferent nerve responses 2,3. This further reduces tear flow and alters tear composition, resulting in pro-inflammatory and proteolytic tears 4 which may elicit apoptosis and autophagy to further damage the ocular surface 5. Reduced tear volume, tear film instability and ocular surface inflammation all contribute to the reduced visual acuity and increased patient discomfort associated with dry eye symptoms in SS 2,6. The male non-obese diabetic mouse (NOD) is commonly used as a model of the autoimmune dacryoadenitis and ocular surface inflammation characteristic of SS. While the ocular manifestations of SS spontaneously develop in the males from 8-10 weeks of age, the female mouse develops a later autoimmune sialoadenitis from 14-16 weeks of age 7. The male NOD mice share many ocular surface system manifestations with SS patients including lymphocytic infiltration of the LG 7,8 , reduced tear flow 7-10 , generation of a proteolytic tear film 7,9,10 , altered distribution and expression of Rab3D 9,11 , reduced myoepithelial cells 12 , loss of extracel...

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“…NOD.ShiLtJ mice are an inbred strain developed by selection for diabetes from F6 of the CTS mouse strain, which was derived from an outbred Jcl:ICR line (Kikutani & Makino, 1992;Makino et al, 1980). In addition to Type I diabetes, autoimmune thyroiditis, and autoimmune peripheral polyneuropathy, NOD.ShiLtJ mice are prone to developing lymphocytic infiltration into the exocrine and endocrine glands, with females exhibiting profound salivary gland penetration, independent of diabetes onset (Ju et al, 2018;Roescher et al, 2012). Salivary and lacrimal gland infiltration occurs at approximately 12 to 16 weeks of age, followed by secretory dysfunction.…”

Section: Introductionmentioning

confidence: 99%

Spontaneous Model of Sjögren's Syndrome in NOD Mice

et al. 2019

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The non‐obese diabetic (NOD) mouse model is the most widely described and validated method for investigating human primary Sjögren's syndrome (SS) and represents a useful model for translational studies. However, the systemic disease manifestation in NOD mice is sensitive to the housing environment, as stress modulates the immune system, so it is essential to confirm that readouts are robust, reproducible, and sensitive to known clinical treatments. This protocol describes the establishment of the spontaneous NOD model of SS and underscores the necessity of model validation to ensure that the housing environment is compatible. © 2019 by John Wiley & Sons, Inc.

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NOD and NOR mice exhibit comparable development of lacrimal gland secretory dysfunction but NOD mice have more severe autoimmune dacryoadenitis

Cited by 17 publications

References 58 publications

Inhibition of Cathepsin S Reduces Lacrimal Gland Inflammation and Increases Tear Flow in a Mouse Model of Sjögren’s Syndrome

Inhibition of Cathepsin S Reduces Lacrimal Gland Inflammation and Increases Tear Flow in a Mouse Model of Sjögren’s Syndrome

Cathepsin S activation contributes to elevated CX3CL1 (fractalkine) levels in tears of a Sjögren’s syndrome murine model

Spontaneous Model of Sjögren's Syndrome in NOD Mice

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