Cyclooxygenase inhibition abrogates aeroallergen-induced immune tolerance by suppressing prostaglandin I2 receptor signaling

Abstract

Background The prevalence of allergic diseases doubled in developed countries in the last several decades. Cyclooxygenase (COX) inhibiting drugs augmented allergic diseases in mice by increasing allergic sensitization and memory immune responses. However, whether COX inhibition can promote allergic airway diseases by inhibiting immune tolerance is not known. Objective To determine the role of the COX pathway and PGI2 signaling through the PGI2 receptor (IP) in aeroallergen-induced immune tolerance. Methods Wild type (WT) BALB/c mice and IP KO mice were aerosolized with ovalbumin (OVA) to induce immune tolerance prior to immune sensitization with an intraperitoneal injection of OVA/alum. The COX inhibitor indomethacin or vehicle was administered in drinking water to inhibit enzyme activity during the sensitization phase. Two weeks after sensitization, the mice were challenged with OVA aerosols. Mouse bronchoalveolar lavage fluid was harvested for cell counts and Th2 cytokine measurements. Results WT mice treated with indomethacin had greater numbers of total cells, eosinophils, and lymphocytes, and increased IL-5 and IL-13 protein expression in BAL fluid compared to vehicle-treated mice. Similarly, IP KO mice had augmented inflammation and Th2 cytokine responses compared to WT mice. In contrast, the PGI2 analog cicaprost attenuated the anti-tolerance effect of COX inhibition. Conclusion COX inhibition abrogated immune tolerance by suppressing PGI2 IP signaling, suggesting that PGI2 signaling promotes immune tolerance and clinical use of COX inhibiting drugs may increase the risk of developing allergic diseases.

Prostaglandin I2Signaling and Inhibition of Group 2 Innate Lymphoid Cell Responses

“…In this in vivo model, iloprost-treated DCs downregulated Th2 differentiation from naive T cells and were also unable to boost effector cytokine production in primed Th2 cells (14). Furthermore, PGI2 was critical to immune tolerance induced by mucosal exposure to antigen in an mouse model of allergic airway inflammation (49). Although these studies revealed that PGI 2 has important immunomodulatory effects on DCs and T cells, our novel results indicate that PGI 2 has profound effects on ILC2 cytokine protein expression and the number of ILC2s in the lung following acute allergen-challenge without sensitization.…”

“…In addition, an IP antagonist increased eosinophil adhesion to endothelial cells (48). In the ovalbumin model, IP 2/2 mice had significantly augmented pulmonary proinflammatory Th2 cytokine expression, airway mucus, and airway responsiveness compared with WT mice in both acute and chronic allergen-induced inflammation models (17,18,49).…”

Lipidmediatoren und ihre Rolle bei Entzündungen und Allergien

“…Andererseits kann es aber auch zusätzlich die entzündungsauflösende Phase des Infekts initiieren (Shinomiya et al 2001). Prostaglandin I2 scheint einen bronchoprotektiven, antiinflammatorischen und antiallergischen Effekt zu haben, der durch COX-Hemmer aufgehoben wird (Zhou et al 2014) (s. 7 Abschn. 7.2.3).…”

Synopsis

“…In der vorher erwähnten Studie von Zhou et al (2014) Inhalation von PGE2 vor Allergen-Challenge reduzierte bei allergischen Asthmatikern sowohl die Früh-als auch die Spätantworten auf das inhalierte Allergen (Pavord und Tattersfield 1995), unterdrückte die Allergen-induzierte eosinophile Inflammation sowie die bronchiale Hyperreaktivität (Gauvreau et al 1999). Ebenfalls nach Inhalation von PGE2 beobachtete man eine Reduktion von PGD2, jenem Prostaglandin, das durch Mastzellenaktivierung sezerniert wird.…”