Skip to main content
placeholder image

Clusterin seals the ocular surface barrier in mouse dry eye

Journal Article


Download full-text (Open Access)

Abstract


  • Dry eye is a common disorder caused by inadequate hydration of the ocular surface that results in disruption of barrier function. The homeostatic protein clusterin (CLU) is prominent at fluid-tissue interfaces throughout the body. CLU levels are reduced at the ocular surface in human inflammatory disorders that manifest as severe dry eye, as well as in a preclinical mouse model for desiccating stress that mimics dry eye. Using this mouse model, we show here that CLU prevents and ameliorates ocular surface barrier disruption by a remarkable sealing mechanism dependent on attainment of a critical all-or-none concentration. When the CLU level drops below the critical all-or-none threshold, the barrier becomes vulnerable to desiccating stress. CLU binds selectively to the ocular surface subjected to desiccating stress in vivo, and in vitro to the galectin LGALS3, a key barrier component. Positioned in this way, CLU not only physically seals the ocular surface barrier, but it also protects the barrier cells and prevents further damage to barrier structure. These findings define a fundamentally new mechanism for ocular surface protection and suggest CLU as a biotherapeutic for dry eye.

Authors


  •   Bauskar, Aditi (external author)
  •   Mack, Wendy J. (external author)
  •   Mauris, Jerome (external author)
  •   Argüeso, Pablo (external author)
  •   Heur, Martin (external author)
  •   Nagel, Barbara A. (external author)
  •   Kolar, Grant R. (external author)
  •   Gleave, Martin E. (external author)
  •   Nakamura, Takahiro (external author)
  •   Kinoshita, Shigeru (external author)
  •   Moradian-Oldak, Janet (external author)
  •   Panjwani, Noorjahan (external author)
  •   Pflugfelder, Stephen (external author)
  •   Mark R Wilson
  •   Fini, M Elizabeth. (external author)
  •   Jeong, Shinwu (external author)

Publication Date


  • 2015

Citation


  • Bauskar, A., Mack, W. J., Mauris, J., Argueso, P., Heur, M., Nagel, B. A., Kolar, G. R., Gleave, M. E., Nakamura, T., Kinoshita, S., Moradian-Oldak, J., Panjwani, N., Pflugfelder, S. C., Wilson, M. R., Fini, M. Elizabeth. & Jeong, S. (2015). Clusterin seals the ocular surface barrier in mouse dry eye. PLoS One, 10 (9), e0138958-1-e0138958-24.

Scopus Eid


  • 2-s2.0-84946934891

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=1581&context=ihmri

Ro Metadata Url


  • http://ro.uow.edu.au/ihmri/559

Has Global Citation Frequency


Start Page


  • e0138958-1

End Page


  • e0138958-24

Volume


  • 10

Issue


  • 9

Place Of Publication


  • United States

Abstract


  • Dry eye is a common disorder caused by inadequate hydration of the ocular surface that results in disruption of barrier function. The homeostatic protein clusterin (CLU) is prominent at fluid-tissue interfaces throughout the body. CLU levels are reduced at the ocular surface in human inflammatory disorders that manifest as severe dry eye, as well as in a preclinical mouse model for desiccating stress that mimics dry eye. Using this mouse model, we show here that CLU prevents and ameliorates ocular surface barrier disruption by a remarkable sealing mechanism dependent on attainment of a critical all-or-none concentration. When the CLU level drops below the critical all-or-none threshold, the barrier becomes vulnerable to desiccating stress. CLU binds selectively to the ocular surface subjected to desiccating stress in vivo, and in vitro to the galectin LGALS3, a key barrier component. Positioned in this way, CLU not only physically seals the ocular surface barrier, but it also protects the barrier cells and prevents further damage to barrier structure. These findings define a fundamentally new mechanism for ocular surface protection and suggest CLU as a biotherapeutic for dry eye.

Authors


  •   Bauskar, Aditi (external author)
  •   Mack, Wendy J. (external author)
  •   Mauris, Jerome (external author)
  •   Argüeso, Pablo (external author)
  •   Heur, Martin (external author)
  •   Nagel, Barbara A. (external author)
  •   Kolar, Grant R. (external author)
  •   Gleave, Martin E. (external author)
  •   Nakamura, Takahiro (external author)
  •   Kinoshita, Shigeru (external author)
  •   Moradian-Oldak, Janet (external author)
  •   Panjwani, Noorjahan (external author)
  •   Pflugfelder, Stephen (external author)
  •   Mark R Wilson
  •   Fini, M Elizabeth. (external author)
  •   Jeong, Shinwu (external author)

Publication Date


  • 2015

Citation


  • Bauskar, A., Mack, W. J., Mauris, J., Argueso, P., Heur, M., Nagel, B. A., Kolar, G. R., Gleave, M. E., Nakamura, T., Kinoshita, S., Moradian-Oldak, J., Panjwani, N., Pflugfelder, S. C., Wilson, M. R., Fini, M. Elizabeth. & Jeong, S. (2015). Clusterin seals the ocular surface barrier in mouse dry eye. PLoS One, 10 (9), e0138958-1-e0138958-24.

Scopus Eid


  • 2-s2.0-84946934891

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=1581&context=ihmri

Ro Metadata Url


  • http://ro.uow.edu.au/ihmri/559

Has Global Citation Frequency


Start Page


  • e0138958-1

End Page


  • e0138958-24

Volume


  • 10

Issue


  • 9

Place Of Publication


  • United States