Abstract
Prostaglandin E2 (PGE2) is produced in the skin and is suggested to play a role in the regulation of cutaneous immune homeostasis and responses. However, the multifaceted functions of PGE2 continue to elude our understanding, especially because of the multiplicity of PGE2 receptors—EP1, EP2, EP3, and EP4. While cAMP-elevating EP4 is known to activate the functions of cutaneous dendritic cells (DCs), including Langerhans cells (LCs) and dermal DCs, the role of cAMP-suppressing EP3 in this process remains unknown. Here we demonstrated that an EP3 receptor selective agonist, ONO-AE-248, inhibited chemotaxis and co-stimulatory molecule expressions of DCs in vitro. A suboptimal dose of antigen was sufficient to induce contact hypersensitivity in EP3-deficient mice. Intriguingly, EP3 deficiency did not impair skin inflammation at all when the antigen dose was sufficiently high. EP3 limited the functions of cutaneous DCs only when the antigen dose was low. In contrast to EP4, the observed unappreciated function of EP3 may stabilize the cutaneous DCs to halt the impetuous response to a suboptimal dose of antigen. Taken together, PGE2-EP3 signaling is essential for fine-tuning excessive skin inflammation by restricting DC functions.
Highlights
The skin is continually exposed to multiple foreign antigens throughout life and it exerts antigen-specific immune responses in which skin dendritic cells (DCs) play an important role as antigen-presenting cells (APCs) [1]
These findings suggest that Prostaglandin E2 (PGE2) may have opposite effects on DC functions, possibly through EP3 signaling, which is consistent with the cAMPlowering effect of EP3, differing from EP4
There have been many reports on the activators of cutaneous DCs to initiate contact hypersensitivity (CHS), such as tumor necrosis factor, IL-1, and IL-18 [3], it remains unclear how the homeostasis of cutaneous DCs is maintained in relation to CHS
Summary
The skin is continually exposed to multiple foreign antigens throughout life and it exerts antigen-specific immune responses in which skin dendritic cells (DCs) play an important role as antigen-presenting cells (APCs) [1]. DCs in the skin are roughly divided into three subsets: Langerhans cells (LCs) in the epidermis and Langerin+ or Langerin- DCs in the dermis [2]. These cutaneous DCs play a central role in the immunity and tolerance of the skin. Responding to foreign antigen, cutaneous DCs migrate to draining lymph nodes undergoing terminal differentiation and maturation. Matured cutaneous DCs activate naive T cells to induce antigen-specific effector/ memory T cells in the lymph nodes [3]. The migration and maturation of cutaneous DCs are, crucial for the initiation of specific immune responses in the skin
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