Interferon-γ treatment in vitro elicits some of the changes in cathepsin S and antigen presentation characteristic of lacrimal glands and corneas from the NOD mouse model of Sjögren’s Syndrome

Meng, Zhen; Klinngam, Wannita; Edman, Maria C.

doi:10.1371/journal.pone.0184781

Cited by 25 publications

(40 citation statements)

References 46 publications

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“…Gene expression of Ctss, together with the pro-inflammatory cytokines, Ifng and Tnf, were significantly elevated in NOD mouse LG ( Fig. 2A) consistent with previous reports 13 . No changes in Cx3cl1 gene expression were observed ( Fig.…”

Section: Cx3cl1 and Ctss Are Increased In Nod Mousesupporting

confidence: 91%

“…previously demonstrated increased IFN-γ in tears of male NOD mice 13 . From mouse corneal cross sections, we found that CX3CL1 was mainly distributed in the corneal epithelium.…”

Section: Ifn-γ Treatment Increases Cx3cl1 In Hce-t Cells and Culture mentioning

confidence: 78%

“…The elevated CX3CL1 found in the tears of NOD mice is likely due in part to the presence of CX3CL1 in apical secretory compartments also enriched in CTSS (Fig. 2B), which may expose membrane-bound CX3CL1 to increased active CTSS also present in these compartments for shedding in tears 13 . IFN-γ is also elevated in tears of NOD mice with autoimmune dacryoadenitis and in patients with primary SS 13 .…”

Section: Discussionmentioning

confidence: 99%

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

Guo

Janga

et al. 2020

Sci Rep

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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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Section: Cx3cl1 and Ctss Are Increased In Nod Mousesupporting

confidence: 91%

“…previously demonstrated increased IFN-γ in tears of male NOD mice 13 . From mouse corneal cross sections, we found that CX3CL1 was mainly distributed in the corneal epithelium.…”

Section: Ifn-γ Treatment Increases Cx3cl1 In Hce-t Cells and Culture mentioning

confidence: 78%

Section: Discussionmentioning

confidence: 99%

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

Guo

Janga

et al. 2020

Sci Rep

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“…Cathepsins degrade ECM proteins, including collagens, laminins, and proteoglycans. [76][77][78][79] Additionally, NID1 binding to the BM is impaired after cleavage by CTSS, 80 which was transcriptionally enhanced in kidney AMR 27 and in response to IFNɣ [81][82][83] . In PTECs, CTSS and LGMN were upregulated by TNFα and IFNɣ.…”

Section: Discussionmentioning

confidence: 99%

Proteomics Reveals Extracellular Matrix Injury in the Glomeruli and Tubulointerstitium of Kidney Allografts with Early Antibody-Mediated Rejection

Clotet-Freixas

McEvoy

Batruch

et al. 2020

Preprint

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Antibody-mediated rejection (AMR) accounts for >50% of kidney allograft losses. AMR is caused by donor-specific antibodies (DSA) against HLA and non-HLA antigens in the glomeruli and the tubulointerstitium, which together with inflammatory cytokines such as tumor necrosis factor alpha (TNFα) and interferon gamma (IFNɣ), trigger graft injury. Unfortunately, the mechanisms governing cell-specific injury in AMR remain unclear. We studied 30 for-cause kidney biopsies with early AMR, acute cellular rejection or acute tubular necrosis ('non-AMR').We laser-captured and microdissected glomeruli and tubulointerstitium, and subjected them to unbiased proteome analysis. 120/2026 glomerular and 180/2399 tubulointerstitial proteins were significantly differentially expressed in AMR vs. non-AMR biopsies (P<0.05). Basement membrane and extracellular matrix (ECM) proteins were significantly decreased in both AMR compartments. We verified decreased glomerular and tubulointerstitial LAMC1 expression, and decreased glomerular NPHS1 and PTPRO expression in AMR. Cathepsin-V (CTSV) was predicted to cleave ECM-proteins in the AMR glomeruli, and CTSL, CTSS and LGMN in the tubulointerstitium. We identified galectin-1, an immunomodulatory protein upregulated in the AMR glomeruli and linked to the ECM. Anti-HLA class-I antibodies significantly increased CTSV expression, and galectin-1 expression and secretion, in human glomerular endothelial cells.Glutathione S-transferase omega-1 (GSTO1), an ECM-modifying enzyme, was significantly increased in the AMR tubulointerstitium, and in TNFα-treated proximal tubular epithelial cells.IFNɣ and TNFα significantly increased CTSS and LGMN expression in these cells. Basement membranes are often remodeled in chronic AMR, and we demonstrated that this remodeling begins early in glomeruli and tubulointerstitium. Targeting ECM-remodeling in AMR may represent a new therapeutic opportunity. 3 SIGNIFICANCE STATEMENTAntibody-mediated rejection (AMR) accounts for >50% of kidney allograft loss, and is caused by donor-specific antibodies against HLA antigens, which induce maladaptive responses in the kidney glomeruli and tubulointerstitium. This is the first unbiased proteomics analysis of lasercaptured/microdissected glomeruli and tubulointerstitium from 30 indication kidney biopsies with early AMR, acute cellular rejection or acute tubular necrosis. >2,000 proteins were quantified in each compartment. We discovered that basement membrane and extracellular matrix (ECM) proteins were significantly decreased in both AMR compartments. Two ECM-modifying proteins,LGALS1 and GSTO1, were significantly increased in glomeruli and tubulointerstitium, respectively. LGALS1 and GSTO1 were upregulated by anti-HLA antibodies or AMR-related cytokines in primary kidney cells, and may represent therapeutic targets to ameliorate ECMremodeling in AMR.with gene expression alterations. 27 However, compartment-specific molecular alterations, or changes in proteome composition/expression are unknown. To address this gap, we conducted a ...

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“…Activation. CatS is essential in MHC II antigen processing and presentation [92,93]. Indeed, CatS null mice show a considerable variation in generation of MHC II-bound Ii fragments, and presentation due to the fact that the Ii degradation in professional APCs is substantially diminished, where CatS is abundantly expressed [94,95].…”

Section: Cats In Mhc II Antigen Presenting and Cd4 + T-cellmentioning

confidence: 99%

Involvement of Cathepsins in Innate and Adaptive Immune Responses in Periodontitis

Wang

et al. 2020

Evidence-Based Complementary and Alternative Medicine

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Periodontitis is an infectious disease whereby the chronic inflammatory process of the periodontium stimulated by bacterial products induces specific host cell responses. The activation of the host cell immune system upregulates the production of inflammatory mediators, comprising cytokines and proteolytic enzymes, which contribute to inflammation and bone destruction. It has been well known that periodontitis is related to systemic inflammation which links to numerous systemic diseases, including diabetes and arteriosclerosis. Furthermore, periodontitis has been reported in association with neurodegenerative diseases such as Alzheimer’s disease (AD) in the brain. Regarding immune responses and inflammation, cathepsin B (CatB) plays pivotal role for the induction of IL-1β, cathepsin K- (CatK-) dependent active toll-like receptor 9 (TLR9) signaling, and cathepsin S (CatS) which involves in regulating both TLR signaling and maturation of the MHC class II complex. Notably, both the production and proteolytic activities of cathepsins are upregulated in chronic inflammatory diseases, including periodontitis. In the present review, we focus on the roles of cathepsins in the innate and adaptive immune responses within periodontitis. We believe that understanding the roles of cathepsins in the immune responses in periodontitis would help to elucidate the therapeutic strategies of periodontitis, thus benefit for reduction of systemic diseases as well as neurodegenerative diseases in the global aging society.

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Interferon-γ treatment in vitro elicits some of the changes in cathepsin S and antigen presentation characteristic of lacrimal glands and corneas from the NOD mouse model of Sjögren’s Syndrome

Cited by 25 publications

References 46 publications

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

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

Proteomics Reveals Extracellular Matrix Injury in the Glomeruli and Tubulointerstitium of Kidney Allografts with Early Antibody-Mediated Rejection

Involvement of Cathepsins in Innate and Adaptive Immune Responses in Periodontitis

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