mPGES1-Dependent Prostaglandin E2 (PGE2) Controls Antigen-Specific Th17 and Th1 Responses by Regulating T Autocrine and Paracrine PGE2 Production

Abstract

The integration of inflammatory signals is paramount in controlling the intensity and duration of immune responses. Eicosanoids, particularly PGE, are critical molecules in the initiation and resolution of inflammation and in the transition from innate to acquired immune responses. Microsomal PGE synthase 1 (mPGES1) is an integral membrane enzyme whose regulated expression controls PGE levels and is highly expressed at sites of inflammation. PGE is also associated with modulation of autoimmunity through altering the IL-23/IL-17 axis and regulatory T cell (Treg) development. During a type II collagen-CFA immunization response, lack of mPGES1 impaired the numbers of CD4 regulatory (Treg) and Th17 cells in the draining lymph nodes. Ag-experienced mPGES1 CD4 cells showed impaired IL-17A, IFN-γ, and IL-6 production when rechallenged ex vivo with their cognate Ag compared with their wild-type counterparts. Additionally, production of PGE by cocultured APCs synergized with that of Ag-experienced CD4 T cells, with mPGES1 competence in the APC compartment enhancing CD4 IL-17A and IFN-γ responses. However, in contrast with CD4 cells that were Ag primed in vivo, exogenous PGE inhibited proliferation and skewed IL-17A to IFN-γ production under Th17 polarization of naive T cells in vitro. We conclude that mPGES1 is necessary in vivo to mount optimal Treg and Th17 responses during an Ag-driven primary immune response. Furthermore, we uncover a coordination of autocrine and paracrine mPGES1-driven PGE production that impacts effector T cell IL-17A and IFN-γ responses.

T cell–intrinsic prostaglandin E2-EP2/EP4 signaling is critical in pathogenic TH17 cell–driven inflammation

“… 67 Quite recently, it was also reported that mPGES1 is involved in generation of antigen-specific T H 17 cells by regulating PGE 2 production in a T-cell autocrine and paracrine manner. 68 Our present findings combined with these findings suggest that PGE 2 plays an important role in psoriasis through regulation of antigen-specific pathogenic T H 17 cells.…”

Mechanisms of immune evasion in bladder cancer

“…Recent studies suggest that inhibition of mPGES1 activity resulted in reduced PD-L1 expression in myeloid cells infiltrating bladder tumor tissue [33]. Furthermore, expression of mPGES1 is necessary for induction of T regs and IL-17-producing T cells during primary immune response [103]. Altogether, these data indicate that targeting mPGES1 in bladder cancer could reduce the tumor-associated immunosuppression and improve the efficacy of cancer immunotherapy.…”

Prostaglandin receptor EP4 expression by Th17 cells is associated with high disease activity in ankylosing spondylitis

“…It remains unknown which mechanisms trigger Th17 cell accumulation in AS. PGE 2 can induce Th17 cells through EP2 and EP4 receptor signaling [21][22][23][24][25][26]. It has been recently shown that EP2 and EP4 signaling is critical in Th17mediated autoimmune inflammation of the skin [25].…”