Increased Cathepsin S activity associated with decreased protease inhibitory capacity contributes to altered tear proteins in Sjögren’s Syndrome patients

Abstract

Cathepsin S (CTSS) activity is elevated in Sjögren’s Syndrome (SS) patient tears. Here we tested whether protease inhibition and cystatin C (Cys C) levels are reduced in SS tears, which could lead to enhanced CTSS-driven degradation of tear proteins. CTSS activity against Cys C, LF and sIgA was tested in SS or healthy control tears. Tears from 156 female subjects (33, SS; 33, rheumatoid arthritis; 31, other autoimmune diseases; 35, non-autoimmune dry eye (DE); 24, healthy controls) were analyzed for CTSS activity and Cys C, LF, and sIgA levels. Cys C and LF showed enhanced degradation in SS tears supplemented with recombinant CTSS, but not supplemented healthy control tears. CTSS activity was significantly increased, while Cys C, LF and sIgA levels were significantly decreased, in SS tears compared to other groups. While tear CTSS activity remained the strongest discriminator of SS in autoimmune populations, combining LF and CTSS improved discrimination of SS beyond CTSS in DE patients. Reductions in Cys C and other endogenous proteases may enhance CTSS activity in SS tears. Tear CTSS activity is reconfirmed as a putative biomarker of SS in an independent patient cohort while combined LF and CTSS measurements may distinguish SS from DE patients.

Cathepsin S Alters the Expression of Pro-Inflammatory Cytokines and MMP-9, Partially through Protease—Activated Receptor-2, in Human Corneal Epithelial Cells

“…To study whether CTSS affects pro-inflammatory cytokine gene expression, human corneal epithelial cells from the HCE-T cell line were treated with recombinant human CTSS at an enzymatic activity comparable to that we detect at the 90th–95th percentile (18,000 Relative Fluorescence Units or RFU per 500 µL of cell medium) in SS patient tears [ 9 ] (see Methods for a detailed explanation). Cells were treated with CTSS for 2, 4, 8, and 24 h. The cell viability after 24 h of CTSS treatment was 97.3 ± 5.2% (mean ± SEM) relative to untreated cells ( n = 3).…”

“…These mediators are also found in tears and conjunctival epithelium [ 15 ], and it is thought that their release from the inflamed LG may impact the ocular surface. The activity of CTSS, a cysteine endopeptidase, is highly increased in the tears of SS patients [ 9 , 59 ]. Here, we show that CTSS is also able, at activity levels found in SS patient tears, to acutely stimulate pro-inflammatory gene and protein expression in a human corneal epithelial cell line.…”

“…Cathepsin S (CTSS), a lysosomal protease, participates in many physiological processes including protein catabolism, major histocompatibility complex class II - antigen presentation and extracellular matrix degradation [ 7 , 8 ]. We have previously demonstrated that CTSS is elevated specifically in the tears of SS patients relative to patients with other autoimmune diseases or SS-independent dry eye [ 9 ]. CTSS is implicated in the pathology of other inflammatory and autoimmune diseases such as atherosclerosis [ 10 , 11 ], rheumatoid arthritis [ 12 ], multiple sclerosis [ 13 ], bronchial asthma and chronic obstructive pulmonary disease [ 14 ].…”

Molecular Regulatory Mechanism of Exocytosis in the Salivary Glands

“…Patients with Sjögren’s syndrome show significant reduction in RAB3D expression, but not RAB8A, as well as the mislocalization of RAB3D from the apical to the basolateral region in salivary gland acinar cells [ 49 , 105 ] and in lacrimal gland acinar cells [ 48 ]. The enzymatic activity of Cathepsin S is upregulated in tears from Sjögren’s syndrome patients, as seen in Rab3d −/− and NOD mice [ 106 , 107 ]. Taken together, RAB expression seems to be altered in the exocrine glands of patients with Sjögren’s syndrome.…”

Estudio de inhibidores peptídicos de proteasas aislados de alimentos de origen vegetal: potenciales aplicaciones como agentes anticoagulantes, anti-infectivos naturales y capacidad protectora del Factor de Crecimiento Epidérmico

“…Se ha demostrado también que la catepsina S desempeña un rol fundamental en la presentación de antígenos clase II del Complejo Mayor de Histocompatibilidad (MHC) ya que la inhibición de la catepsina S disminuye significativamente la respuesta a antígenos, hecho que convierte a esta enzima en un nuevo blanco para drogas contra el asma y ciertas enfermedades autoinmunes (Zhou, 2016;Edman et al, 2018). Las catepsinas han sido también relacionadas en procesos de invasión tumoral y en las metástasis (Tamhane, Lu, Maelandsmo, Haugen, & Brix, 2016 También se ha observado con gran interés la participación de las proteasas cisteínicas en un amplio rango de enfermedades parasitarias como la malaria, la enfermedad de Chagas y la esquistosomiasis (Rosenthal, 2011;Ndao et al, 2013).…”