Prostaglandin E2 via EP4/IL-1R inhibits Th17 cell differentiation during the efferocytosis of infected cells

Author(s)

Naiara Naiana Dejani

• Document type: Doctoral Thesis
• Press: Ribeirão Preto.
• Institution: Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto (PCARP/BC)
• Defense date: 2016-09-01

Examining board members

Alexandra Ivo de Medeiros; Alexandre Salgado Basso; Cristina Ribeiro de Barros Cardoso; Aristóbolo Mendes da Silva

• Advisor: Alexandra Ivo de Medeiros

Abstract

Phagocytosis of apoptotic cells promotes the synthesis of mediators such as transforming growth factor (TGF-β), prostaglandin E2 (PGE2) and interleukin-10 (IL-10), which are important for the differentiation of regulatory T cells (Treg). However, phagocytosis of infected apoptotic cells by dendritic cells results in the synthesis of cytokines such as TGF-Beta;, IL-6 and IL-23 known to promote T helper 17 cell (Th17) differentiation. Preliminary results obtained by our group showed that, along with these cytokines, PGE2 is also produced during efferocytosis of infected cells. However, nothing was known regarding the involvement of this prostanoid on Th17 differentiation process. Thus, our hypothesis was based on the study of intracellular signaling mechanism by which PGE2, via E prostanoid receptor (EP), could be involved in the differentiation of Th17 cells in the context of efferocytosis. Our results show that, besides TGF-β and IL-6 production, phagocytosis of Escherichia coli-infected apoptotic cells by dendritic cells induces the synthesis of high levels of PGE2 and IL-1β, as previously described as Th17 inducers. However, unlike our original hypothesis, the presence of PGE2 inhibited the differentiation of Th17 cells, while the absence of this prostanoid resulted in increased percentage and number of this phenotype. Naive CD4+ T cells treated with EP2/EP4 agonists and antagonists demonstrated that the suppressive effect of PGE2 is primarily mediated by the EP4 receptor, via activation of cAMP and PKA. Furthermore, PGE2-EP4 negatively modulates the expression of IL-1β receptor (IL-1R), impairing Th17 differentiation. Also, in vivo, during Citrobacter rodentium infection, inhibition of PGE2 synthesis or EP4 receptor blockade resulted in increased population of Th17 cells and greater expression of antimicrobial peptides in colon, as well as a drastic reduction in bacterial load. Finally, all these data demonstrate that PGE2, via EP4-PKA-IL-1R, suppresses Th17 differentiation in vitro and in vivo, and reveals a novel mechanism in the modulation of adaptive immune response of Th17 cells promoted by PGE2 in the context of efferocytosis. (AU)

• FAPESP's process: 12/23580-0 - Differentiation of Th17 cells during phagocytosis of infected apoptotic cells: Determination of intracellular signaling pathways via PGE2 and EP receptors
• Grantee: Naiara Naiana Dejani
• Support Opportunities: Scholarships in Brazil - Doctorate