4.7 Article

CDCP1 regulates retinal pigmented epithelial barrier integrity for the development of experimental autoimmune uveitis

Journal

JCI INSIGHT
Volume 7, Issue 18, Pages -

Publisher

AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/jci.insight.157038

Keywords

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Funding

  1. NIH [EY025373, EY030111, EY031087, P30EY025585]
  2. Research to Prevent Blindness
  3. Cleveland Eye Bank Foundation grant
  4. National Multiple Sclerosis Society Fellowship [FG-1908-34934]

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CDCP1, highly expressed on the surface of cancer cells, was found to be present on retinal pigment epithelial (RPE) cells. It interacts with CD6 on T cells, inducing cytoskeleton remodeling and focal adhesion disruption in RPE cells, leading to the development of autoimmune uveitis.
Cub domain-containing protein 1 (CDCP1) is a protein that is highly expressed on the surface of many cancer cells. However, its distribution in normal tissues and its potential roles in nontumor cells are poorly understood. We found that CDCP1 is present on both human and mouse retinal pigment epithelial (RPE) cells. CDCP1-KO mice developed attenuated retinal inflammation in a passive model of autoimmune uveitis, with disrupted tight junctions and infiltrating T cells detected in RPE flat mounts from WT but not CDCP1-KO mice during EAU development. Mechanistically, we discovered that CDCP1 on RPE cells was upregulated by IFN-gamma in vitro and after EAU induction in vivo. CD6 stimulation induced increased RPE barrier permeability of WT but not CDCP1-knockdown (CDCP1-KD) RPE cells, and activated T cells migrated through WT RPE monolayers more efficiently than the CDCP1-KD RPE monolayers. In addition, CD6 stimulation of WT but not the CDCP1-KD RPE cells induced massive stress fiber formation and focal adhesion disruption to reduce cell barrier tight junctions. These data suggest that CDCP1 on RPE cells interacts with CD6 on T cells to induce RPE cytoskeleton remodeling and focal adhesion disruption, which open up the tight junctions to facilitate T cell infiltration for the development of uveitis.

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