Effects of Cathepsin S Inhibition in the Age-Related Dry Eye Phenotype

Purpose Aged C57BL/6J (B6) mice have increased levels of cathepsin S, and aged cathepsin S (Ctss−/−) knockout mice are resistant to age-related dry eye. This study investigated the effects of cathepsin S inhibition on age-related dry eye disease. Methods Female B6 mice aged 15.5 to 17 months were randomized to receive a medicated diet formulated by mixing the RO5461111 cathepsin S inhibitor or a standard diet for at least 12 weeks. Cornea mechanosensitivity was measured with a Cochet–Bonnet esthesiometer. Ocular draining lymph nodes and lacrimal glands (LGs) were excised and prepared for histology or assayed by flow cytometry to quantify infiltrating immune cells. The inflammatory foci (>50 cells) were counted under a 10× microscope lens and quantified using the focus score. Goblet cell density was investigated in periodic acid–Schiff stained sections. Ctss−/− mice were compared to age-matched wild-type mice. Results Aged mice subjected to cathepsin S inhibition or Ctss−/− mice showed improved conjunctival goblet cell density and cornea mechanosensitivity. There was no change in total LG focus score in the diet or Ctss−/− mice, but there was a lower frequency of CD4+IFN-γ+ cell infiltration in the LGs. Furthermore, aged Ctss−/− LGs had an increase in T central memory, higher numbers of CD19+B220−, and fewer CD19+B220+ cells than wild-type LGs. Conclusions Our results indicate that therapies aimed at decreasing cathepsin S can ameliorate age-related dry eye disease with a highly beneficial impact on the ocular surface. Further studies are needed to investigate the role of cathepsin S during aging.

[1]  A. Trevani,et al.  An ocular Th1 immune response promotes corneal nerve damage independently of the development of corneal epitheliopathy , 2023, Journal of Neuroinflammation.

[2]  D. Bentley,et al.  A randomized, double-blind, placebo-controlled, parallel group study on the effects of a cathepsin S inhibitor in primary Sjögren's syndrome. , 2023, Rheumatology.

[3]  C. Trujillo-Vargas,et al.  Ectopic lymphoid structures in the aged lacrimal glands. , 2023, Clinical immunology.

[4]  Natalia Frankowska,et al.  Proteolysis dysfunction in the process of aging and age-related diseases , 2022, Frontiers in Aging.

[5]  Jielin Deng,et al.  The role of age-associated autonomic dysfunction in inflammation and endothelial dysfunction. , 2022, GeroScience.

[6]  M. Komatsu,et al.  Impaired GATE16-mediated exocytosis in exocrine tissues causes Sjögren’s syndrome-like exocrinopathy , 2022, Cellular and Molecular Life Sciences.

[7]  F. Paulsen,et al.  Immune phenotype of the CD4+ T cells in the aged lymphoid organs and lacrimal glands , 2022, GeroScience.

[8]  S. Hamm-Alvarez,et al.  Cathepsin S is a novel target for age-related dry eye. , 2021, Experimental eye research.

[9]  S. Hamm-Alvarez,et al.  Phenylephrine increases tear cathepsin S secretion in healthy murine lacrimal gland acinar cells through an alternative secretory pathway. , 2021, Experimental eye research.

[10]  Z. Ryoo,et al.  Overexpression of cathepsin S exacerbates lupus pathogenesis through upregulation TLR7 and IFN-α in transgenic mice , 2021, Scientific Reports.

[11]  C. D. de Paiva,et al.  Age‐related changes in ocular mucosal tolerance: Lessons learned from gut and respiratory tract immunity , 2021, Immunology.

[12]  C. D. de Paiva,et al.  The ocular surface immune system through the eyes of aging. , 2021, The ocular surface.

[13]  Jiyang Cai,et al.  Modulation of Oxidative Stress and Inflammation in the Aged Lacrimal Gland. , 2020, The American journal of pathology.

[14]  A. Trevani,et al.  Transient tear hyperosmolarity disrupts the neuroimmune homeostasis of the ocular surface and facilitates dry eye onset , 2020, Immunology.

[15]  D. Bowdish,et al.  Single cell and tissue-transcriptomic analysis of murine bladders reveals age- and TNFα–dependent but microbiota-independent tertiary lymphoid tissue formation , 2020, Mucosal Immunology.

[16]  P. Amouyel,et al.  Circulating proteomic signature of early death in heart failure patients with reduced ejection fraction , 2019, Scientific Reports.

[17]  D. Saban,et al.  Complement and CD4+ T cells drive context-specific corneal sensory neuropathy , 2019, eLife.

[18]  J. A. MacKay,et al.  Inhibition of Cathepsin S Reduces Lacrimal Gland Inflammation and Increases Tear Flow in a Mouse Model of Sjögren’s Syndrome , 2019, Scientific Reports.

[19]  A. Bruckbauer,et al.  B cells rapidly target antigen and surface-derived MHCII into peripheral degradative compartments , 2019, Journal of Cell Science.

[20]  S. Pflugfelder,et al.  Age-associated Antigen-Presenting Cell Alterations Promote Dry-Eye Inducing Th1 cells , 2018, Mucosal Immunology.

[21]  Hyunji Lee,et al.  Down-regulation of cathepsin S and matrix metalloproteinase-9 via Src, a non-receptor tyrosine kinase, suppresses triple-negative breast cancer growth and metastasis , 2018, Experimental & Molecular Medicine.

[22]  A. Trevani,et al.  The mucosal surfaces of both eyes are immunologically linked by a neurogenic inflammatory reflex involving TRPV1 and substance P , 2018, Mucosal Immunology.

[23]  M. Stepp,et al.  Reduced intraepithelial corneal nerve density and sensitivity accompany desiccating stress and aging in C57BL/6 mice , 2018, Experimental eye research.

[24]  Michel Theron,et al.  Cathepsin S inhibition suppresses autoimmune‐triggered inflammatory responses in macrophages , 2017, Biochemical pharmacology.

[25]  S. Hamm-Alvarez,et al.  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 , 2017, PloS one.

[26]  Michel Theron,et al.  Pharmacodynamic Monitoring of RO5459072, a Small Molecule Inhibitor of Cathepsin S , 2017, Front. Immunol..

[27]  P. Gregersen,et al.  Increased Cathepsin S in Prdm1−/− dendritic cells alters TFH repertoire and contributes to lupus , 2017, Nature Immunology.

[28]  W. Haap,et al.  Cathepsin S inhibition combines control of systemic and peripheral pathomechanisms of autoimmune tissue injury , 2017, Scientific Reports.

[29]  W. Haap,et al.  Cathepsin S inhibition combines control of systemic and peripheral pathomechanisms of autoimmune tissue injury , 2017, Scientific Reports.

[30]  M. Surette,et al.  Age-Associated Microbial Dysbiosis Promotes Intestinal Permeability, Systemic Inflammation, and Macrophage Dysfunction , 2017, Cell host & microbe.

[31]  M. Giordano,et al.  Mucosal immune tolerance at the ocular surface in health and disease , 2017, Immunology.

[32]  A. Trevani,et al.  Mucosal tolerance disruption favors disease progression in an extraorbital lacrimal gland excision model of murine dry eye. , 2016, Experimental eye research.

[33]  Changjun Wang,et al.  Interferon-gamma deficiency protects against aging-related goblet cell loss , 2016, Oncotarget.

[34]  C. Okamoto,et al.  Imbalanced Rab3D versus Rab27 increases cathepsin S secretion from lacrimal acini in a mouse model of Sjögren's Syndrome. , 2016, American journal of physiology. Cell physiology.

[35]  S. Pflugfelder,et al.  Interferon-γ-Induced Unfolded Protein Response in Conjunctival Goblet Cells as a Cause of Mucin Deficiency in Sjögren Syndrome. , 2016, The American journal of pathology.

[36]  Changjun Wang,et al.  Dexamethasone Drug Eluting Nanowafers Control Inflammation in Alkali-Burned Corneas Associated With Dry Eye , 2016, Investigative ophthalmology & visual science.

[37]  Ø. Grimstad.  Tumor Necrosis Factor and the Tenacious α. , 2016, JAMA dermatology.

[38]  A. Trevani,et al.  Desiccating stress‐induced disruption of ocular surface immune tolerance drives dry eye disease , 2016, Clinical and experimental immunology.

[39]  Lyndon Jones,et al.  Degradation of proteoglycan 4/lubricin by cathepsin S: Potential mechanism for diminished ocular surface lubrication in Sjögren's syndrome , 2015, Experimental eye research.

[40]  S. Vanzulli,et al.  Restoring conjunctival tolerance by topical nuclear factor-κB inhibitors reduces preservative-facilitated allergic conjunctivitis in mice. , 2014, Investigative ophthalmology & visual science.

[41]  W. Mack,et al.  Tear Cathepsin S as a Candidate Biomarker for Sjögren's Syndrome , 2014, Arthritis & rheumatology.

[42]  C. Franceschi,et al.  Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. , 2014, The journals of gerontology. Series A, Biological sciences and medical sciences.

[43]  E. A. Volpe,et al.  Ocular surface disease and dacryoadenitis in aging C57BL/6 mice. , 2014, The American journal of pathology.

[44]  W. Haap,et al.  Cathepsin S inhibition suppresses systemic lupus erythematosus and lupus nephritis because cathepsin S is essential for MHC class II-mediated CD4 T cell and B cell priming , 2013, Annals of the rheumatic diseases.

[45]  S. Akira,et al.  Enhanced apoptosis by disruption of the STAT3-IκB-ζ signaling pathway in epithelial cells induces Sjögren's syndrome-like autoimmune disease. , 2013, Immunity.

[46]  Irene Puga,et al.  Marginal zone B cells: virtues of innate-like antibody-producing lymphocytes , 2013, Nature Reviews Immunology.

[47]  M. Cancro,et al.  B cell maintenance and function in aging. , 2012, Seminars in immunology.

[48]  E. Ingelsson,et al.  Association between serum cathepsin S and mortality in older adults. , 2011, JAMA.

[49]  M. Percival,et al.  Therapeutic dosing of an orally active, selective cathepsin S inhibitor suppresses disease in models of autoimmunity. , 2011, Journal of autoimmunity.

[50]  K. Schenke-Layland,et al.  Increased expression of cathepsins and obesity-induced proinflammatory cytokines in lacrimal glands of male NOD mouse. , 2010, Investigative ophthalmology & visual science.

[51]  Richard Weindruch,et al.  Gene expression profiling of aging in multiple mouse strains: identification of aging biomarkers and impact of dietary antioxidants , 2009, Aging cell.

[52]  B. Blomberg,et al.  Effects of aging on B cell function. , 2009, Current opinion in immunology.

[53]  G. Baron,et al.  EULAR Sjögren's syndrome disease activity index: development of a consensus systemic disease activity index for primary Sjögren's syndrome , 2009, Annals of the rheumatic diseases.

[54]  C. Stichel,et al.  Upregulation of cathepsin S in the aging and pathological nervous system of mice , 2008, Brain Research.

[55]  H. Luebbert,et al.  Inflammatory processes in the aging mouse brain: Participation of dendritic cells and T-cells , 2007, Neurobiology of Aging.

[56]  De-Quan Li,et al.  Dry eye-induced conjunctival epithelial squamous metaplasia is modulated by interferon-gamma. , 2007, Investigative ophthalmology & visual science.

[57]  L. Zhuo,et al.  Expression and upregulation of cathepsin S and other early molecules required for antigen presentation in activated hepatic stellate cells upon IFN-gamma treatment. , 2007, Biochimica et biophysica acta.

[58]  C. Kublin,et al.  Age-dependent alterations in mouse exorbital lacrimal gland structure, innervation and secretory response. , 2005, Experimental eye research.

[59]  A. Rudensky,et al.  Cathepsin S Controls MHC Class II-Mediated Antigen Presentation by Epithelial Cells In Vivo1 , 2005, The Journal of Immunology.

[60]  C. Weyand,et al.  Ageing, autoimmunity and arthritis: T-cell senescence and contraction of T-cell repertoire diversity – catalysts of autoimmunity and chronic inflammation , 2003, Arthritis research & therapy.

[61]  J. Buring,et al.  Prevalence of dry eye syndrome among US women. , 2003, American journal of ophthalmology.

[62]  E. Weber,et al.  Human cathepsin S, but not cathepsin L, degrades efficiently MHC class II-associated invariant chain in nonprofessional APCs , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[63]  C. Franceschi,et al.  Centenarians as a model for healthy aging. , 2003, Biochemical Society transactions.

[64]  N. Ishimaru,et al.  Cathepsin S inhibitor prevents autoantigen presentation and autoimmunity. , 2002, The Journal of clinical investigation.

[65]  R. Klein,et al.  Prevalence of and risk factors for dry eye syndrome. , 2000, Archives of ophthalmology.

[66]  L. Devi,et al.  Inflammatory Mediators Regulate Cathepsin S in Macrophages and Microglia: A Role in Attenuating Heparan Sulfate Interactions , 1999, Molecular medicine.

[67]  G. Dranoff,et al.  Cathepsin S required for normal MHC class II peptide loading and germinal center development. , 1999, Immunity.

[68]  R. Mitchell,et al.  Cathepsin S activity regulates antigen presentation and immunity. , 1998, The Journal of clinical investigation.

[69]  E. A. Volpe,et al.  Topical interferon-gamma neutralization prevents conjunctival goblet cell loss in experimental murine dry eye. , 2014, Experimental eye research.