Activated prostaglandin D-2 receptors on macrophages enhance neutrophil recruitment into the lung

作者：Jandl Katharina; Stacher Elvira; Balint Zoltan; Sturm Eva Maria; Maric Jovana; Peinhaupt Miriam; Luschnig Petra; Aringer Ida; Fauland Alexander; Konya Viktoria; Dahlen Sven Erik; Wheelock Craig E; Kratky Dagmar; Olschewski Andrea; Marsche Gunther; Schuligoi Rufina; Heinemann Akos^*

来源：Journal of Allergy and Clinical Immunology, 2016, 137(3): 833-843.

DOI：10.1016/j.jaci.2015.11.012

• D-type prostanoid receptor 1
• D-type prostanoid receptor 2/chemoattractant receptor-homologous molecule expressed on T(H)2 cells
• prostaglandin D-2
• hematopoietic prostaglandin D synthase
• macrophages
• pulmonary inflammation
• neutrophils

Background: Prostaglandin (PG) D-2 is an early-phase mediator in inflammation, but its action and the roles of the 2 D-type prostanoid receptors (DPs) DP1 and DP2 (also called chemoattractant receptor-homologous molecule expressed on T(H)2 cells) in regulating macrophages have not been elucidated to date.
Objective: We investigated the role of PGD(2) receptors on primary human macrophages, as well as primary murine lung macrophages, and their ability to influence neutrophil action in vitro and in vivo.
Methods: In vitro studies, including migration, Ca2+ flux, and cytokine secretion, were conducted with primary human monocyte-derived macrophages and neutrophils and freshly isolated murine alveolar and pulmonary interstitial macrophages. In vivo pulmonary inflammation was assessed in male BALB/c mice.
Results: Activation of DP1, DP2, or both receptors on human macrophages induced strong intracellular Ca2+ flux, cytokine release, and migration of macrophages. In a murine model of LPS-induced pulmonary inflammation, activation of each PGD(2) receptor resulted in aggravated airway neutrophilia, tissue myeloperoxidase activity, cytokine contents, and decreased lung compliance. Selective depletion of alveolar macrophages abolished the PGD(2)-enhanced inflammatory response. Activation of PGD(2) receptors on human macrophages enhanced the migratory capacity and prolonged the survival of neutrophils in vitro. In human lung tissue specimens both DP1 and DP2 receptors were located on alveolar macrophages along with hematopoietic PGD synthase, the rate-limiting enzyme of PGD(2) synthesis.
Conclusion: For the first time, our results show that PGD(2) markedly augments disease activity through its ability to enhance the proinflammatory actions of macrophages and subsequent neutrophil activation.

• 出版日期2016-3