Activated prostaglandin D₂ receptors on macrophages enhance neutrophil recruitment into the lung

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• 作者：Katharina Jandl ; MSc^a ; Elvira Stacher ; MD^b ; Zoltá ; n Bá ; lint ; PhD^c ; Eva Maria Sturm ; PhD^a ; Jovana Maric ; MSc^a ; Miriam Peinhaupt ; MSc^a ; Petra Luschnig ; PhD^a ; Ida Aringer ; MD^a ; ^d ; Alexander Fauland ; PhD^e ; Viktoria Konya ; PhD^a ; ^f ; Sven-Erik Dahlen ; PhD^g ; Craig E. Wheelock ; PhD^e ; Dagmar Kratky ; PhD^h ; Andrea Olschewski ; MD^c ; Gunther Marsche ; PhD^a ; Rufina Schuligoi ; PhD^a ; Akos Heinemann ; MD^a ; ^{akos.heinemann@medunigraz.at" class="auth_mail" title="E-mail the corresponding author}
• 关键词：D-type prostanoid receptor 1 ; D-type prostanoid receptor 2/chemoattractant receptor&ndash ; homologous molecule expressed on TH2 cells ; prostaglandin D2 ; hematopoietic prostaglandin D synthase ; macrophages ; pulmonary inflammation ; neutrophils
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：2016
• 出版时间：March 2016
• 年：2016
• 卷：137
• 期：3
• 页码：833-843
• 全文大小：2956 K

文摘

Prostaglandin (PG) D₂ 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_H2 cells) in regulating macrophages have not been elucidated to date.

Objective

We investigated the role of PGD₂ 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 PGD₂ receptor resulted in aggravated airway neutrophilia, tissue myeloperoxidase activity, cytokine contents, and decreased lung compliance. Selective depletion of alveolar macrophages abolished the PGD₂-enhanced inflammatory response. Activation of PGD₂ 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 PGD₂ synthesis.

Conclusion

For the first time, our results show that PGD₂ markedly augments disease activity through its ability to enhance the proinflammatory actions of macrophages and subsequent neutrophil activation.