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E-Prostanoid 3 Receptor Deletion Improves Pulmonary Host Defense and Protects Mice from Death in Severe Streptococcus pneumoniae Infection¹

David M. Aronoff^2,*, Casey Lewis, Carlos H. Serezani, Kathryn A. Eaton, Deepti Goel, John C. Phipps, Marc Peters-Golden and Peter Mancuso

Divisions of ^* Infectious Diseases and Pulmonary and Critical Care Medicine, Department of Internal Medicine, and Department of Microbiology and Immunology, University of Michigan Health System, Ann Arbor, MI 48109; and Department of Environmental Health Sciences, University of Michigan, Ann Arbor, MI 48109

Prostaglandins (PGs) are potent lipid mediators that are produced during infections and whose synthesis and signaling networks present potential pharmacologic targets for immunomodulation. PGE₂ acts through the ligation of four distinct G protein-coupled receptors, E-prostanoid (EP) 1–4. Previous in vitro and in vivo studies demonstrated that the activation of the G_s-coupled EP2 and EP4 receptors suppresses inflammatory responses to microbial pathogens through cAMP-dependent signaling cascades. Although it is speculated that PGE₂ signaling via the G_i-coupled EP3 receptor might counteract EP2/EP4 immunosuppression in the context of bacterial infection (or severe inflammation), this has not previously been tested in vivo. To address this, we infected wild-type (EP3^+/+) and EP3^–/– mice with the important respiratory pathogen Streptococcus pneumoniae or injected mice i.p. with LPS. Unexpectedly, we observed that EP3^–/– mice were protected from mortality after infection or LPS. The enhanced survival observed in the infected EP3^–/– mice correlated with enhanced pulmonary clearance of bacteria; reduced accumulation of lung neutrophils; lower numbers of circulating blood leukocytes; and an impaired febrile response to infection. In vitro studies revealed improved alveolar macrophage phagocytic and bactericidal capacities in EP3^–/– cells that were associated with an increased capacity to generate NO in response to immune stimulation. Our studies underscore the complex nature of PGE₂ immunomodulation in the context of host-microbial interactions in the lung. Pharmacological targeting of the PGE₂-EP3 axis represents a novel area warranting greater investigative interest in the prevention and/or treatment of infectious diseases.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants HL078727, HL077417, and HL058897.

² Address correspondence and reprint requests to Dr. David M. Aronoff, 4618-C Medical Sciences Building II, 1150 West Medical Center Drive, Ann Arbor, MI 48109-5623. E-mail address: daronoff{at}umich.edu

³ Abbreviations used in this paper: EP, E-prostanoid; BAL, bronchoalveolar lavage; BALF, BAL fluid; H2DCF, 2',7'-dichlorodihydrofluorescein diacetate; i.t., intratracheal; KO, knockout; ROI, reactive oxygen intermediate; T_b, core body temperature; WT, wild type.