**1. Introduction**

Allergic inflammation arises from both innate and adaptive immune responses that are characterized by an increase in the production of type 2 cytokines, such as interleukin (IL)-4, IL-5, IL-9, and IL-13 [1,2]. These cytokines are important in the pathogenesis of allergic diseases such as asthma, atopic dermatitis, allergic rhinitis, and food allergy. IL-4 can cause isotype switching of B cells to IgE production and drives naïve CD4+ T cells to a Th2 phenotype. IL-5 is the most important cytokine in eosinophil differentiation, migration, and survival, which is significant because eosinophils are critical in allergic inflammation pathogenesis. IL-9 has important effects on mast cell development, while IL-13 is a central mediator of airway responsiveness and mucus production, both cardinal features of asthma. An increased understanding of allergen-induced inflammation over the past decade reveals that activated CD4+ Th2 cells alone are not solely responsible for propagating allergic disease. In addition to CD4+ Th2 cells, group 2 innate lymphoid cells (ILC2) also produce IL-5, IL-9, and IL-13 and, in special circumstances, may also secrete IL-4 [3]. Importantly, ILC2 produces IL-5 at a significantly greater level than even CD4+ Th2 cells [4]. In patients with severe asthma, Th1, Th17, and CD8+ cytotoxic lymphocytes and neutrophils may even be observed [5].

In this review, we will focus on the role of prostaglandin (PG)I2 in regulating the allergic inflammatory pathway detailed in the preceding paragraph. As we will discuss, endogenous PGI2 restrains allergen-induced inflammatory responses, and both in vivo and in vitro studies in mice suggest that exogenous PGI2 may be a target for the treatment of allergic diseases such as asthma. PGI2 is one of the five primary prostaglandins. Prostaglandins are eicosanoids, active lipid compounds that are produced through arachidonic acid metabolism via the cyclooxygenase (COX) pathway. The sequential metabolism

**Citation:** Patel, K.; Peebles, R.S., Jr. Prostacyclin Regulation of Allergic Inflammation. *Biomedicines* **2022**, *10*, 2862. https://doi.org/10.3390/ biomedicines10112862

Academic Editor: Stanislawa Bazan-Socha

Received: 30 September 2022 Accepted: 4 November 2022 Published: 9 November 2022

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**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

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of arachidonic acid leading to prostaglandin production may be constitutive or induced in response to pathophysiological conditions, such as inflammation [6]. Arachidonic acid is released from the nuclear and cytoplasmic plasma membrane via the action of phospholipase A2 (PLA2). COX-1 and COX-2 convert arachidonic acid to an unstable intermediary, PGG2, which can then be converted to PGH2 by COX and peroxidase activity [7]. Tissue-specific enzymes and isomerases convert PGH2 into the five primary prostanoids, which include PGE2, PGD2, PGF2α, PGI2, and thromboxane A2. Whether a specific prostaglandin is produced or not is dependent upon the expression of the synthase for that prostaglandin in that tissue.

PGI2 is most commonly referred to as prostacyclin, and we will use this terminology in this review. Prostacyclin was discovered in 1976 by Vane and Moncada [8]. Prostacyclin is generated by PGI synthase (PGIS) converting PGH2 into PGI2, and PGIS is primarily, but not exclusively, localized in endothelial cells, where it is most abundantly expressed (Figure 1) [7]. Traditionally, prostacyclin has been recognized as an effective vasodilator within both systemic and pulmonary circulations, as it elicits smooth muscle relaxation and has been observed to have anti-platelet aggregatory effects [9]. These characteristics are what led to the rise of prostacyclin analogs, such as iloprost, trepostinil, and epoprostenol, being used clinically in the treatment of pulmonary arterial hypertension [10–12]. For the FDA-approved prostacyclin analogs, iloprost can be administered through either the inhaled or intravenous routes, while epoprostenol is administered intravenously. Treprostinil can be given subcutaneously, intravenously, or orally [13,14]. While beraprost and cicaprost are also potent prostacyclin analogs, neither has been approved by the FDA [13].

**Figure 1.** The pathway of prostacyclin production. The arrows show the downstream enzymatic pathways.
