Abstract
Purpose: :
Suppressors of cytokine signaling (SOCS) proteins are detected in the retina and are elevated in ocular inflammatory diseases. To better understand their functions in the retina, we have generated a transgenic rat strain that constitutively express SOCS1 in the retina (SOCS1-TR). We have also generated mice with targeted deletion of SOCS3 in CD4+ T cells (SOCS3KO). Here, we have described phenotypes of these rodent strains and investigated the roles of SOCS1 and SOCS3 in mechanisms of ocular diseases.
Methods: :
SOCS1-TR rats were generated as described (J. Immunol. 162: 510-517) and effects of SOCS1 on insulin metabolism or PI3K/AKT signaling were investigated in SOCS1-TR primary retinal cells that were stimulated with insulin. The SOCS3KO strain was generated by cross of SOCS3fl/fl with CD4-Cre mice. Inhibitory effect on STAT3 signaling was confirmed by Western blot analysis of IL-6 stimulated T cells. Experimental autoimmune uveitis (EAU) was induced with IRBP and intracellular cytokine expression was detected/quantified by FACS and ELISA.
Results: :
(i) We show that over-expression of SOCS1 induces insulin resistance in the retina. In contrast to the high basal pAKT activity in freshly isolated WT retinal cells, SOCS1-TR retinal cells exhibit low basal pAKT activity and diminished ability of insulin to activate AKT pathways. (ii) Compared to EAU in wild type mice, disease in SOCS3KO is very mild and the relative resistance to EAU is associated with diminished ability of SOCS3KO mice to generate Th17 cells.
Conclusions: :
(i) SOCS-mediated insulin-resistance, as indicated by inhibition of basally active PI3K/AKT signaling in retina of SOCS1-TR rats is validated in retinal cells over-expressing SOCS1, suggesting that SOCS1-TR rat strain maybe a useful model for studying the role of retinal insulin-resistance in diabetic retinopathy. (ii) Decreased EAU severity in SOCS3-deficient mice underscores the central roles played by STAT3 and Th17 cells in uveitis and suggests that SOCS3 mimetics could be used for the treatment of ocular inflammatory diseases.
Keywords: autoimmune disease • uveitis-clinical/animal model • immunomodulation/immunoregulation