Targeting the Opposing Roles of Prostaglandin E2 Receptors, EP3 and EP4, in the Pathogenesis of Type One Diabetes

Project Summary/Abstract
Type one diabetes (T1D) is an autoimmune condition characterized by the progressive destruction of insulin-
producing β cells in the pancreas, leading to onset of clinical hyperglycemia and chronic dysglycemia. T1D can
be managed for decades with constant blood glucose monitoring and administration of exogenous insulin.
However, there is still no real cure to prevent or reverse onset of disease. Many current treatments have targeted
the immune system to prevent action of autoreactive lymphocytes, however concerns for patients remain over
immunosuppression. Additionally, recent literature has highlighted the level of β-cell dysfunction that also
contributes to disease pathogenesis. Therefore, treatments designed to target both β-cell health and
autoimmunity may provide the greatest potential for prevention and reversal of T1D. Prostaglandin E2 (PGE2), a
lipid signaling molecule, possesses the capacity to modulate both the immune system and the β cells, through
the action of two receptors, EP3 and EP4. These two receptors have near equal affinity for the PGE2 ligand, but
couple to opposing intracellular pathways. Blockade of EP3 tone and enhancement of EP4 tone have previously
been demonstrated to promote β-cell proliferation and survival in both mouse and human islets ex vivo.
Additionally, in vivo, antagonism of EP3 enhances β-cell proliferation, mass, and oxidative stress responses in
a mouse model of type 2 diabetes. In the pathogenesis of T1D, β cells are exposed to high levels of oxidative
stress in the presence of proinflammatory cytokines from islet-infiltrating immune cells. This stress, along with
direct destruction by cytotoxic T cells, results in a significant loss of β-cell mass. Therefore, modulating the EP3
and EP4 receptors pathways may be able to provide β cells significant protection against this attack to prevent
loss or promote regeneration of β-cell mass. Furthermore, the primary function of PGE2 is to serve as an
immunomodulator, and it can affect immune cell phenotype and function at various stages throughout the
inflammatory response. At later stages of inflammation, sustained PGE2 production from macrophages helps
facilitate resolution of inflammation, a process which is hypothesized to be disrupted in autoimmunity. Many of
these pro-resolution activities are mediated via action of EP4, and therefore, enhancement of EP4 tone in the
islet microenvironment may also promote β-cell survival by modulating immune cell activity and allowing proper
resolution of inflammation. Ultimately, the proposed studies will elucidate whether targeting the opposing
pathways of EP3 and EP4 can serve to mitigate β-cell death by promoting pathways associated with β-cell
proliferation and survival, while simultaneously altering the islet microenvironment to favor a less
proinflammatory state. This approach may unlock a novel therapeutic strategy for treating T1D by targeting both
sides of the autoimmune equation at once.

Grant Number: 5F31DK138714-02
NIH Institute/Center: NIH
Principal Investigator: Juliann Burkett