Program

OR17-4

Regulation of Immune-mediated Inflammatory Responses by Prostaglandin E2

[Speaker] Chengcan Yao:1
[Co-author] Sarah Em Howie:1, Adriano G Rossi:1, Shuh Narumiya:2
1:MRC Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, UK, 2:Department of Drug Discovery Medicine, Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan

Background:
PGE2 is a lipid mediator, with both pro- and anti-inflammatory potentials, that interact with distinct receptors. Interestingly, PGE2 receptor EP4/PTGER4 gene polymorphisms are associated with numerous human inflammatory diseases. However, the precise mechanisms for how PGE2 regulates immune-mediated inflammation remain to be elucidated.

Methods:
We systemically investigated molecular and cellular mechanisms for how PGE2 modulates Th1/Th17/Th22 and innate lymphoid cell (ILC) differentiation and function and their roles in inflammatory diseases using in vitro cell culture systems and in vivo animal models.

Results:
We have found that PGE2, through its receptors EP2/EP4, promotes Th1/Th17/Th22 cell-mediated inflammatory responses in mouse models of multiple sclerosis, eczema, psoriasis and chronic colitis (1-4). Mechanistically, we have revealed that PGE2 initiates IL-12Rβ2 and IFN-γR gene transcription and amplifies their signaling to support Th1 differentiation through the EP2/EP4-cAMP-PKA-CREB and PI3K-AKT pathways (2). We further discovered that PGE2 stimulates IL-23R expression through EP2/EP4-cAMP-PKA-CREB signalling, leading to generation of pathogenic Th17 and Th22 cells (3-4). These findings suggest that new therapeutic strategies against immune-mediated chronic inflammation by targeting PGE2 synthesis or receptors are likely.

In contrast, we have also observed that mice deficient in endogenous PGE2 spontaneously resulted in gut barrier disruption, bacterial translocation and systemic inflammation, which was prevented by EP4 agonism. Mechanistically, PGE2-EP4 signaling stimulates IL-22-producing ILCs in the gut. Ablation of EP4 in ILCs exacerbated systemic inflammation which was prevented by exogenous IL-22 (5). These findings offer a new interpretation for the well-known gastrointestinal side effects of NSAIDs and clinical observations on negative consequences of NSAID use in severe inflammatory conditions, but also indicate potential approaches for prevention of NSAID's adverse effects.

Conclusions:
PGE2 has multiple roles in modulation (both facilitating and attenuating) of immune-mediated inflammatory diseases context-dependently of the microenvironmental niches (Figure 1).

References:
1, Yao C, et al. Nat Med. 15:633-640 (2009).
2, Yao C, et al. Nat Commun. 4:1685 (2013).
3, Robb C, et al. J Allergy Clin Immunol. DOI:http://dx.doi.org/10.1016/j.jaci.2017.04.045 (2017).
4, Lee J, et al. Manuscript submitted (2018).
5, Duffin R, et al. Science 351:1333-1338 (2016).

Acknowledgement:
Medical Research Council (UK), Wellcome Trust, and Japan Science and Technology Agency.

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