Increased Expression of Cathepsins and Obesity-Induced Proinflammatory Cytokines in Lacrimal Glands of Male NOD Mouse

Li, Xiaodong; Wu, Kaijin; Edman, Maria C.; Schenke‐Layland, Katja; MacVeigh-Aloni, Michelle; Janga, Srikanth Reddy; Schulz, Bárbara; Hamm‐Alvarez, Sarah F.

doi:10.1167/iovs.09-4523

Cited by 65 publications

(94 citation statements)

References 46 publications

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“…CTSH overexpression typically correlates to macrophage infiltration and a proinflammatory environment in a number of tissues 58, 59. Therefore it is likely that the loss of Ctsh leads to an increase in levels of other cathepsins, such as our observation of increased levels of cathepsin B, which might have a proinflammatory role and is known to play an important role in processing of mast cell proteases 60, 61.…”

Section: Discussionmentioning

confidence: 79%

A mechanistic target of rapamycin complex 1/2 (mTORC1)/V-Akt murine thymoma viral oncogene homolog 1 (AKT1)/cathepsin H axis controls filaggrin expression and processing in skin, a novel mechanism for skin barrier disruption in patients with atopic dermatitis

Naeem¹,

Tommasi²,

Callebaut

et al. 2017

Journal of Allergy and Clinical Immunology

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BackgroundFilaggrin, which is encoded by the filaggrin gene (FLG), is an important component of the skin's barrier to the external environment, and genetic defects in FLG strongly associate with atopic dermatitis (AD). However, not all patients with AD have FLG mutations.ObjectiveWe hypothesized that these patients might possess other defects in filaggrin expression and processing contributing to barrier disruption and AD, and therefore we present novel therapeutic targets for this disease.ResultsWe describe the relationship between the mechanistic target of rapamycin complex 1/2 protein subunit regulatory associated protein of the MTOR complex 1 (RAPTOR), the serine/threonine kinase V-Akt murine thymoma viral oncogene homolog 1 (AKT1), and the protease cathepsin H (CTSH), for which we establish a role in filaggrin expression and processing. Increased RAPTOR levels correlated with decreased filaggrin expression in patients with AD. In keratinocyte cell cultures RAPTOR upregulation or AKT1 short hairpin RNA knockdown reduced expression of the protease CTSH. Skin of CTSH-deficient mice and CTSH short hairpin RNA knockdown keratinocytes showed reduced filaggrin processing, and the mouse had both impaired skin barrier function and a mild proinflammatory phenotype.ConclusionOur findings highlight a novel and potentially treatable signaling axis controlling filaggrin expression and processing that is defective in patients with AD.

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Section: Discussionmentioning

confidence: 79%

A mechanistic target of rapamycin complex 1/2 (mTORC1)/V-Akt murine thymoma viral oncogene homolog 1 (AKT1)/cathepsin H axis controls filaggrin expression and processing in skin, a novel mechanism for skin barrier disruption in patients with atopic dermatitis

Naeem¹,

Tommasi²,

Callebaut

et al. 2017

Journal of Allergy and Clinical Immunology

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“…The study revealed an increased level of cathepsin S at the mRNA level, as well as increased levels of protein as determined by immunofluorescence and activity (Li et al, 2010). In a separate study, deletion of cathepsin S in mice was shown to significantly attenuate the onset of diabetes, thus providing a level of protection (Hsing et al, 2010).…”

Section: Diabetes and Obesitymentioning

confidence: 87%

Cathepsin S: therapeutic, diagnostic, and prognostic potential

Wilkinson

Williams

Scott

et al. 2015

Biological Chemistry

174

139

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Cathepsin S is a member of the cysteine cathepsin protease family. It is a lysosomal protease which can promote degradation of damaged or unwanted proteins in the endo-lysosomal pathway. Additionally, it has more specific roles such as MHC class II antigen presentation, where it is important in the degradation of the invariant chain. Unsurprisingly, mis-regulation has implicated cathepsin S in a variety of pathological processes including arthritis, cancer, and cardiovascular disease, where it becomes secreted and can act on extracellular substrates. In comparison to many other cysteine cathepsin family members, cathepsin S has uniquely restricted tissue expression and is more stable at a neutral pH, which supports its involvement and importance in localised disease microenvironments. In this review, we examine the known involvement of cathepsin S in disease, particularly with respect to recent work indicating its role in mediating pain, diabetes, and cystic fibrosis. We provide an overview of current literature with regards cathepsin S as a therapeutic target, as well as its role and potential as a predictive diagnostic and/or prognostic marker in these diseases.

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“…In an earlier study with the non-obese diabetic (NOD) mouse, a well-established murine model for SS, we demonstrated increased cathepsin S (Ctss) expression and activity in LG acinar cells that was paralleled by elevated tear Ctss activity as compared to control mice (16). Similarly, Ctss gene expression is up-regulated in the early stages of disease and, in contrast to other cathepsins, remains up-regulated throughout the later stages of disease in the C57BL/6.NOD-Aec1Aec2 mouse model of SS (17).…”

Section: Introductionmentioning

confidence: 97%

Tear Cathepsin S as a Candidate Biomarker for Sjögren's Syndrome

Hamm‐Alvarez

Janga

Edman

et al. 2014

Arthritis & Rheumatology

Self Cite

106

108

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Objective The diagnosis of Sjögren's Syndrome (SS) in routine practice is largely a clinical one and requires a high index of suspicion by the treating physician. This great dependence upon clinical judgment frequently leads to delayed diagnosis or misdiagnosis. Tear protein profiles have been proposed as simple and reliable biomarkers for SS diagnosis. Given that cathepsin S activity is increased in the lacrimal glands and tears of NOD mice (a murine model of SS), we explored the clinical utility of using tear cathepsin S (CTSS) activity as a biomarker for SS. Methods A method to measure CTSS activity in tears eluted from Schirmer's strips was developed and validated. Schirmer's tests and CTSS activity measurements were performed on 278 female subjects, including patients with SS (n=73), rheumatoid arthritis (n=79), systemic lupus erythematosus (n=40), blepharitis (n=10), non-specific dry eye (n=31), or other autoimmune diseases (n=12), along with 33 healthy controls. Results Median tear CTSS activity in SS patients was 4.1-fold higher than in patients with non-SS autoimmune diseases, 2.1-fold higher than in patients with non-specific dry eye, and 41.1-fold higher than in healthy controls. Tear CTSS levels were equally elevated in primary and secondary SS independent of the Schirmer's strip values or of circulating anti-SSA or anti-SSB autoantibodies. Conclusion Markedly high levels of tear CTSS activity are suggestive of SS. CTSS activity in tears can be measured in a simple, quick, economical, and non-invasive fashion and may serve as a novel biomarker and indicator of autoimmune dacryoadenitis during the workup for SS.

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Increased Expression of Cathepsins and Obesity-Induced Proinflammatory Cytokines in Lacrimal Glands of Male NOD Mouse

Abstract: Expression of CATS and CATH increases in parallel with proinflammatory cytokines during the development of autoimmune inflammatory disease in the NOD mouse disease model. Tear CATS may represent a biomarker for diagnosis of dacryoadenitis in SjS.

Cited by 65 publications

References 46 publications

A mechanistic target of rapamycin complex 1/2 (mTORC1)/V-Akt murine thymoma viral oncogene homolog 1 (AKT1)/cathepsin H axis controls filaggrin expression and processing in skin, a novel mechanism for skin barrier disruption in patients with atopic dermatitis

A mechanistic target of rapamycin complex 1/2 (mTORC1)/V-Akt murine thymoma viral oncogene homolog 1 (AKT1)/cathepsin H axis controls filaggrin expression and processing in skin, a novel mechanism for skin barrier disruption in patients with atopic dermatitis

Cathepsin S: therapeutic, diagnostic, and prognostic potential

Tear Cathepsin S as a Candidate Biomarker for Sjögren's Syndrome

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