Abstract
A20 is a negative regulator of inflammation and immunity and plays a role in several autoimmune and inflammatory diseases. Here, we demonstrate that A20 overexpression significantly ameliorates severity of EAU by inhibiting the infiltration of Th1 and Th17 cells, and by protecting integrity of the blood retinal barrier. In vitro studies showed that A20 silencing could promote CD4+T cells toward a Th1 and Th17 phenotype. A decreased expression of A20 in CD4+T cells was noticed in active BD patients but not in VKH patients. Furthermore, silencing of A20 in hRPE cells induced the production of IL-6, IL-8, and MCP-1 and downregulated ZO-1 and occludin expression which is mediated by inhibition of MAPK and NF-κB pathways. This study reveals a mechanism by which A20 prevents autoimmune uveitis.
Highlights
Uveitis is an intraocular inflammatory disease that may cause severe visual impairment [1]
We first evaluated the expression of A20 in the retina and retinal pigment epithelium (RPE)-complex of EAU mice on day 0, 7, 14, and 21 following IRBP immunization and found that the expression of A20 was significantly decreased on day 14 (Figures 1A, B)
We demonstrate that the expression of A20 in CD4+T cells from active BD patients is decreased
Summary
Uveitis is an intraocular inflammatory disease that may cause severe visual impairment [1]. A20, called tumor necrosis factor a-induced protein 3(TNFAIP3), is directly induced by TNF-a/ TNFR signaling, and encoded by the TNFAIP3 gene [4] It is known as a deubiquitinating enzyme and acts as a negative regulator on inflammation and immunity by inhibiting the NF-kB signaling pathway downstream of TNFR [4]. Mice lacking A20 in B cells (Tnfaip3flox/flox Cd19-Cre+ mice) spontaneously develop an autoimmune condition similar to SLE, including anti-dsDNA antibodies and glomerular immune-complex deposits [5,6,7]. Mice with an A20 deletion in CD11c+ DCs (Tnfaip3flox/flox Cd11c-Cre+ mice) rapidly develop a significantly disordered immune homeostasis, and showed various phenotypes, such as inflammatory bowel disease, systemic autoimmunity resembling SLE, and multiorgan inflammation [4, 8,9,10]. Mice lacking A20 in their macrophages and granulocytes (Tnfaip3flox/flox Lysm-Cre mice) developed polyarthritis that was associated with collagen-specific autoantibodies and an increased systemic and local cytokine production [11, 12]
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