Resolvin E1 Regulates Th17 Activation and Response to Dendritic Cells

Objectives: T-helper 17 cells (Th17) central to chronic inflammation require dendritic cells (DC) to differentiate. Our hypothesis was that Resolvin E1 (RvE1), a pro-resolution mediator that plays an active role during resolution of inflammation, regulates Th17 proliferation and differentiation by DCs.
Methods: CD4⁺ T cells and CD11c⁺ DCs were isolated from mouse spleens. For Th17 stimulation; T cells were incubated with IL-6/TGF-β1 for 5 days in the plates previously coated with anti-CD3/CD28. For Th17 stimulation by DCs; DCs were incubated with T cells for 5 days and stimulated with Pam₃CSK₄. RvE1 was applied at baseline and on Day 3. DC maturation was assessed by inducing DCs with Pam₃CSK₄ and incubating for 3 days; RvE1 was applied at baseline and on Day 2. Expression of CD80, CD86, CD40, MHC II, ChemR23 by DCs and CD4, CD25, CCR6, CD62L, ChemR23, RORγt and IL-17 by T cells were analyzed by FACS. IL-17A, IL-17F, IL-21, CCL20 and IL-2 secretion by T cells; IL-6 and TGFβ secretions by DCs were measured by multiplex immunoassays.
Results: RvE1 significantly decreased RORγt, IL-17, CCR6, CD62L, CD25 expressions and IL-17A, IL-17F, IL-21, CCL20, IL-2 secretions (p<0.05) suggesting a direct suppression on Th17 proliferation and activation. IL-17A secretion and CD25 expression were significantly reduced by RvE1 (p<0.05) in co-cultures suggesting an inhibition of the Th17 stimulation by DCs. CD4⁺CD25⁺ cell rates decreased to 3.7% from 70% and to 6.4% from 17% in mono- and co-culture experiments respectively; RORγt and IL-17 expressed by CD4⁺CD25⁺ cells decreased significantly (p<0.05). RvE1 further decreased IL-6 and IL-2 levels and increased TGFβ significantly (p<0.05) suggesting an inhibition of DC maturation. Both DCs and T cells expressed ChemR23, the receptor for RvE1.
Conclusions: RvE1 prevents chronic inflammatory response by inhibiting the Th17 differentiation and chemoattraction; T cell selectivity and activation while preventing DC maturation.