Innate lymphocytes, monocytes, regulatory T cells (Tregs) and regulatory B cells (Bregs) suppress CNS autoimmune diseases such as Uveitis or Multiple Sclerosis by secreting IL-10 and IL-35. The activities of these immune suppressive cytokines are regulated by JAK/STAT. In this study, we sought to identify major cell types that produce both cytokines in-vivo and to characterize mechanisms that regulate their production. Compared to innate or Tregs we found that Bregs are the major producers of IL-35 and IL-10 in vivo during ocular inflammatory diseases. We also found that BATF, IFN regulatory factor (IRF)-4, and IRF-8 transcription factors are recruited and bind to AP1-IRF-composite elements (AICEs) of il12a, ebi3, and/or il10 loci, suggesting that these transcription factors contribute to contribute to IL-10 and IL-35 expression in the activated B-cell. We also found that STAT3-dependent and independent pathways control ocular inflammation. These studies suggest that targeting STAT3 pathways and the BATF/IRF-4/IRF-8 axis can be exploited therapeutically to regulate physiological levels of IL-10/IL-35-Bregs and ocular inflammation.
Showing the most recent 10 out of 25 publications
