The Role of the IL-20 Subfamily in Glaucoma

Glaucoma is a common disease that leads to loss of peripheral vision and, if left untreated, ultimately to blindness. While the exact cause(s) of glaucoma is still unknown, two leading risk factors are age and elevated intraocular pressure. Several studies suggest a possible link between glaucoma and inflammation in humans and animal models. In particular, our lab recently identified a T104M mutation in IL-20 receptor-B (IL-20RB) in primary open angle glaucoma patients from a large pedigree. Several of the interleukin- (IL-) 20 family of cytokines and receptors are expressed in ocular tissues including the trabecular meshwork, optic nerve head, and retinal ganglion cells. The DBA/2J mouse develops high intraocular pressures with age and has characteristic optic nerve defects that make it a useful glaucoma model. IL-24 expression is significantly upregulated in the retina of these mice, while IL-20RA expression in the optic nerve is downregulated following pressure-induced damage. The identification of a mutation in the IL-20RB gene in a glaucoma pedigree and changes in expression levels of IL-20 family members in the DBA/2J mouse suggest that disruption of normal IL-20 signaling in the eye may contribute to degenerative processes associated with glaucoma.

[1]  P. Horner,et al.  Early Reduction of Microglia Activation by Irradiation in a Model of Chronic Glaucoma , 2012, PloS one.

[2]  A. Suzumura,et al.  Interleukin-19 Acts as a Negative Autocrine Regulator of Activated Microglia , 2015, PloS one.

[3]  M. Tanito,et al.  Multiplex cytokine analysis of aqueous humor in eyes with primary open-angle glaucoma, exfoliation glaucoma, and cataract. , 2012, Investigative ophthalmology & visual science.

[4]  K. Madden,et al.  Interleukins 19, 20, and 24 Signal through Two Distinct Receptor Complexes , 2002, The Journal of Biological Chemistry.

[5]  V. Baekelandt,et al.  Tackling Glaucoma from within the Brain: An Unfortunate Interplay of BDNF and TrkB , 2015, PloS one.

[6]  K. Rezaei,et al.  Multiplex cytokine analysis reveals elevated concentration of interleukin-8 in glaucomatous aqueous humor. , 2010, Investigative ophthalmology & visual science.

[7]  J. Vranka,et al.  Extracellular matrix in the trabecular meshwork: intraocular pressure regulation and dysregulation in glaucoma. , 2015, Experimental eye research.

[8]  R. Lin,et al.  IL-20 May Contribute to the Pathogenesis of Human Intervertebral Disc Herniation , 2008, Spine.

[9]  Michael G. Anderson,et al.  Interacting loci cause severe iris atrophy and glaucoma in DBA/2J mice , 1999, Nature Genetics.

[10]  J. Salazar,et al.  IOP induces upregulation of GFAP and MHC-II and microglia reactivity in mice retina contralateral to experimental glaucoma , 2012, Journal of Neuroinflammation.

[11]  M. Mochizuki,et al.  Immunological homeostasis of the eye , 2013, Progress in Retinal and Eye Research.

[12]  K. Rajashankar,et al.  Structural basis for receptor sharing and activation by interleukin-20 receptor-2 (IL-20R2) binding cytokines , 2012, Proceedings of the National Academy of Sciences.

[13]  K. Ariizumi,et al.  Molecular Cloning of a Dendritic Cell-associated Transmembrane Protein, DC-HIL, That Promotes RGD-dependent Adhesion of Endothelial Cells through Recognition of Heparan Sulfate Proteoglycans* , 2001, The Journal of Biological Chemistry.

[14]  Michael G. Anderson,et al.  Inherited glaucoma in DBA/2J mice: pertinent disease features for studying the neurodegeneration. , 2005, Visual neuroscience.

[15]  K. Choy,et al.  JAK/STAT pathway mediates retinal ganglion cell survival after acute ocular hypertension but not under normal conditions. , 2007, Experimental eye research.

[16]  David O. Walton,et al.  Datgan, a reusable software system for facile interrogation and visualization of complex transcription profiling data , 2011, BMC Genomics.

[17]  R. T. Hart,et al.  Viscoelastic material properties of the peripapillary sclera in normal and early-glaucoma monkey eyes. , 2005, Investigative ophthalmology & visual science.

[18]  L. Pasquale,et al.  Bupropion Use and Risk of Open-Angle Glaucoma among Enrollees in a Large U.S. Managed Care Network , 2015, PloS one.

[19]  A. Neufeld,et al.  Tumor necrosis factor‐α: A potentially neurodestructive cytokine produced by glia in the human glaucomatous optic nerve head , 2000 .

[20]  J. Samples,et al.  Effect of matrix metalloproteinases activity on outflow in perfused human organ culture. , 1998, Investigative ophthalmology & visual science.

[21]  David J. Calkins,et al.  Quantitative correlation of optic nerve pathology with ocular pressure and corneal thickness in the DBA/2 mouse model of glaucoma. , 2006, Investigative ophthalmology & visual science.

[22]  S. Mckinnon The cell and molecular biology of glaucoma: common neurodegenerative pathways and relevance to glaucoma. , 2012, Investigative ophthalmology & visual science.

[23]  David J. Calkins,et al.  Reduced retina microglial activation and improved optic nerve integrity with minocycline treatment in the DBA/2J mouse model of glaucoma. , 2008, Investigative ophthalmology & visual science.

[24]  Jean P. Gaffney,et al.  Multilevel regulation of matrix metalloproteinases in tissue homeostasis indicates their molecular specificity in vivo. , 2015, Matrix biology : journal of the International Society for Matrix Biology.

[25]  C. Cheung,et al.  Expression profile of inflammatory cytokines in aqueous from glaucomatous eyes , 2012, Molecular vision.

[26]  G. Kitsos,et al.  Refining the primary open‐angle glaucoma GLC1C region on chromosome 3 by haplotype analysis , 2003, Clinical genetics.

[27]  D. Calkins,et al.  Central Visual Pathways in Glaucoma: Evidence for Distal Mechanisms of Neuronal Self-Repair , 2015, Journal of neuro-ophthalmology : the official journal of the North American Neuro-Ophthalmology Society.

[28]  J. Morrison,et al.  Cell proliferation and interleukin-6-type cytokine signaling are implicated by gene expression responses in early optic nerve head injury in rat glaucoma. , 2011, Investigative ophthalmology & visual science.

[29]  T. Wong,et al.  Global prevalence of glaucoma and projections of glaucoma burden through 2040: a systematic review and meta-analysis. , 2014, Ophthalmology.

[30]  J. Flammer,et al.  Targeted preventive measures and advanced approaches in personalised treatment of glaucoma neuropathy , 2010, EPMA Journal.

[31]  A. Rotchford,et al.  Temba glaucoma study: a population-based cross-sectional survey in urban South Africa. , 2003, Ophthalmology.

[32]  M. Wax,et al.  TNF-a and TNF-a Receptor-1 in the Retina of Normal and Glaucomatous Eyes , 2001 .

[33]  K. Yamaki,et al.  Tyrosinase Family Proteins Are Antigens Specific to Vogt-Koyanagi-Harada Disease1 , 2000, The Journal of Immunology.

[34]  A. Sommer,et al.  Relationship between intraocular pressure and primary open angle glaucoma among white and black Americans. The Baltimore Eye Survey. , 1991, Archives of ophthalmology.

[35]  F. Medeiros,et al.  The pathophysiology and treatment of glaucoma: a review. , 2014, JAMA.

[36]  J. Streilein Ocular immune privilege: therapeutic opportunities from an experiment of nature , 2003, Nature Reviews Immunology.

[37]  K. Choi,et al.  Identification of the genes differentially expressed in human dendritic cell subsets by cDNA subtraction and microarray analysis. , 2002, Blood.

[38]  Michael G. Anderson,et al.  High-dose radiation with bone marrow transfer prevents neurodegeneration in an inherited glaucoma. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[39]  R. Tripathi,et al.  Aqueous Humor in Glaucomatous Eyes Contains an Increased Level of TGF-β2 , 1994 .

[40]  G. Howell,et al.  The complex role of neuroinflammation in glaucoma. , 2014, Cold Spring Harbor perspectives in medicine.

[41]  P. Kramer,et al.  Mapping a gene for adult-onset primary open-angle glaucoma to chromosome 3q. , 1997, American journal of human genetics.

[42]  Janey L. Wiggs,et al.  Mutations in genes encoding melanosomal proteins cause pigmentary glaucoma in DBA/2J mice , 2002, Nature Genetics.

[43]  E. Sage,et al.  Overexpression of SPARC in human trabecular meshwork increases intraocular pressure and alters extracellular matrix. , 2013, Investigative ophthalmology & visual science.

[44]  S. John,et al.  Under pressure: cellular and molecular responses during glaucoma, a common neurodegeneration with axonopathy. , 2012, Annual review of neuroscience.

[45]  U. Wegenka IL-20: biological functions mediated through two types of receptor complexes. , 2010, Cytokine & growth factor reviews.

[46]  J. Stein‐Streilein Immune regulation and the eye. , 2008, Trends in immunology.

[47]  H. Kaplan,et al.  Early Involvement of Immune/Inflammatory Response Genes in Retinal Degeneration in DBA/2J Mice , 2010, Ophthalmology and eye diseases.

[48]  Robert N Weinreb,et al.  Risk assessment in the management of patients with ocular hypertension. , 2004, American journal of ophthalmology.

[49]  S. Rutz,et al.  The IL-20 subfamily of cytokines — from host defence to tissue homeostasis , 2014, Nature Reviews Immunology.

[50]  M. Inatani,et al.  Transforming growth factor-β2 levels in aqueous humor of glaucomatous eyes , 2001, Graefe's Archive for Clinical and Experimental Ophthalmology.

[51]  A. Wlodawer,et al.  Crystal Structure of Interleukin-19 Defines a New Subfamily of Helical Cytokines* , 2003, The Journal of Biological Chemistry.

[52]  Yong-feng Yang,et al.  Interleukin-20 receptor expression in the trabecular meshwork and its implication in glaucoma. , 2014, Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics.

[53]  F. Medeiros,et al.  Managing glaucoma in developing countries. , 2011, Arquivos brasileiros de oftalmologia.

[54]  T. Acott,et al.  Extracellular matrix turnover and outflow resistance. , 2009, Experimental eye research.

[55]  J. Morrison,et al.  Friend or foe? Resolving the impact of glial responses in glaucoma. , 2009, Journal of glaucoma.

[56]  Ted S Acott,et al.  Current understanding of conventional outflow dysfunction in glaucoma , 2012, Current opinion in ophthalmology.

[57]  J. Salazar,et al.  Microglia in mouse retina contralateral to experimental glaucoma exhibit multiple signs of activation in all retinal layers , 2014, Journal of Neuroinflammation.

[58]  D. Hodge,et al.  Long-term trends in glaucoma-related blindness in Olmsted County, Minnesota. , 2014, Ophthalmology.

[59]  J C Morrison,et al.  The anatomy and pathophysiology of the optic nerve head in glaucoma. , 2001, Journal of glaucoma.

[60]  Xing Liu,et al.  Damage to the blood-aqueous barrier in eyes with primary angle closure glaucoma , 2010, Molecular vision.

[61]  M. Wax,et al.  TNF-alpha and TNF-alpha receptor-1 in the retina of normal and glaucomatous eyes. , 2001, Investigative ophthalmology & visual science.

[62]  M. Vetter,et al.  Early microglia activation in a mouse model of chronic glaucoma , 2011, The Journal of comparative neurology.

[63]  J Katz,et al.  A population-based evaluation of glaucoma screening: the Baltimore Eye Survey. , 1991, American journal of epidemiology.

[64]  Joan W. Miller,et al.  Etanercept, a Widely Used Inhibitor of Tumor Necrosis Factor-α (TNF- α), Prevents Retinal Ganglion Cell Loss in a Rat Model of Glaucoma , 2012, PloS one.

[65]  Michael G. Anderson,et al.  By Altering Ocular Immune Privilege, Bone Marrow–derived Cells Pathogenically Contribute to DBA/2J Pigmentary Glaucoma , 2003, The Journal of experimental medicine.

[66]  S. Fauser,et al.  The effect of previous surgery and topical eye drops for primary open-angle glaucoma on cytokine expression in aqueous humor , 2014, Graefe's Archive for Clinical and Experimental Ophthalmology.

[67]  Chien-Feng Li,et al.  Anti–IL-20 Monoclonal Antibody Suppresses Breast Cancer Progression and Bone Osteolysis in Murine Models , 2012, The Journal of Immunology.

[68]  T. Acott,et al.  Effects of mechanical stretching on trabecular matrix metalloproteinases. , 2001, Investigative Ophthalmology and Visual Science.

[69]  Vittorio Porciatti,et al.  Radiation treatment inhibits monocyte entry into the optic nerve head and prevents neuronal damage in a mouse model of glaucoma. , 2012, The Journal of clinical investigation.

[70]  William Cepurna,et al.  Understanding mechanisms of pressure-induced optic nerve damage , 2005, Progress in Retinal and Eye Research.

[71]  X (inbo) Li,et al.  Intraocular pressure homeostasis: maintaining balance in a high-pressure environment. , 2014, Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics.

[72]  M. Wax,et al.  Matrix metalloproteinases and tumor necrosis factor α in glaucomatous optic nerve head , 2000 .

[73]  Michael V. Boland,et al.  Risk factors and open-angle glaucoma: classification and application. , 2007, Journal of glaucoma.

[74]  Stuart C. Sealfon,et al.  Cytokine Response Is Determined by Duration of Receptor and Signal Transducers and Activators of Transcription 3 (STAT3) Activation* , 2012, The Journal of Biological Chemistry.

[75]  P. Iserovich,et al.  Pro-inflammatory cytokines in glaucomatous aqueous and encysted Molteno implant blebs and their relationship to pressure. , 2013, Investigative ophthalmology & visual science.

[76]  D. Aaronson,et al.  A Road Map for Those Who Don't Know JAK-STAT , 2002, Science.

[77]  J. Alvarado,et al.  Monocyte modulation of aqueous outflow and recruitment to the trabecular meshwork following selective laser trabeculoplasty. , 2010, Archives of ophthalmology.

[78]  H. Quigley,et al.  Neuronal death in glaucoma , 1999, Progress in Retinal and Eye Research.

[79]  M. Fautsch,et al.  Proteome analysis of human aqueous humor. , 2010, Investigative ophthalmology & visual science.

[80]  M. Kuehn Immune phenomena in glaucoma and conformational disorders: why is the second eye not involved? , 2014, Journal of glaucoma.

[81]  P. Foster,et al.  The definition and classification of glaucoma in prevalence surveys , 2002, The British journal of ophthalmology.

[82]  J. Schuman,et al.  Activation of a tissue-specific stress response in the aqueous outflow pathway of the eye defines the glaucoma disease phenotype , 2001, Nature Medicine.