Harnessing prostaglandin E2 signaling to ameliorate autoimmunity

Abstract

The etiology of most autoimmune diseases remains unknown; however, shared among them is a disruption of immunoregulation. Prostaglandin lipid signaling molecules possess context-dependent immunoregulatory properties, making their role in autoimmunity difficult to decipher. For example, prostaglandin E₂ (PGE₂) can function as an immunosuppressive molecule as well as a proinflammatory mediator in different circumstances, contributing to the expansion and activation of T cell subsets associated with autoimmunity. Recently, PGE₂ was shown to play important roles in the resolution and post-resolution phases of inflammation, promoting return to tissue homeostasis. We propose that PGE₂ plays both proinflammatory and pro-resolutory roles in the etiology of autoimmunity, and that harnessing this signaling pathway during the resolution phase might help prevent autoimmune attack.

Keywords: PGE(2); T cells; anti-inflammatory; inflammation; macrophage; proinflammatory.

Figure 1.. Model for the role of PGE₂ in modulating normal progression towards inflammation.

Prostaglandin E₂ plays a complex role in modulating inflammation. In the initiating stages, PGE₂ is produced by damaged cells within a tissue/organ leading to the recruitment of neutrophils that produce proinflammatory cytokines and leukotrienes, resulting in monocyte recruitment to the site of inflammation. Macrophage efferocytosis of dying neutrophils induces macrophage-specific production of PGE₂, which is essential for facilitating a phenotypic switch that favors production of specialized pro-resolving lipid mediators such as LXA4 [61,62]. In addition, recruited macrophages secrete factors such as IL-6, IL-4, IFNγ , and IL-12 that can alter T cell polarization and activation states, as well as promote DC migration and expression of costimulatory molecules such as OX40L, CD80/CD86, or CD40. There is also evidence that PGE₂ contributes to macrophage production of anti-inflammatory factors such as IL-6, IL-1β, and IL-23, as well as blockade of further innate immune activation, allowing proper restoration of tissue homeostasis. We posit that the diverse actions of PGE₂ throughout the progression of inflammation are achieved via effects of signaling through disparate receptors, changes in the activity of synthetic enzymes (i.e. COX-1/COX-2, PGES-1/mPGES-1) and the cell of origin, as well as the general inflammatory context under which PGE₂ is acting (for example, acute injury versus the post-resolution immunosuppressive phase). This figure was created with Biorender.com