EP4 and EP2 Receptor Activation of Protein Kinase A by Prostaglandin E2 Impairs Macrophage Phagocytosis of Clostridium sordellii

Authors

  • Lisa M. Rogers,

    1. Division of Infectious Diseases, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI, USA
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  • Tennille Thelen,

    1. Department of Immunology, University of Washington School of Medicine, Seattle, WA, USA
    2. Immunology Program, Benaroya Research Institute at Virginia Mason, Seattle, WA, USA
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  • Krystle Fordyce,

    1. Division of Infectious Diseases, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI, USA
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  • Emilie Bourdonnay,

    1. Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI, USA
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  • Casey Lewis,

    1. Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI, USA
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  • Han Yu,

    1. College of Biological, Chemical Sciences and Engineering, Jiaxing University, Jiaxing, China
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  • Junyong Zhang,

    1. College of Biological, Chemical Sciences and Engineering, Jiaxing University, Jiaxing, China
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  • Jingli Xie,

    1. College of Biological, Chemical Sciences and Engineering, Jiaxing University, Jiaxing, China
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  • Carlos H. Serezani,

    1. Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA
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  • Marc Peters-Golden,

    1. Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI, USA
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  • David M. Aronoff

    Corresponding author
    1. Division of Infectious Diseases, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI, USA
    2. Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI, USA
    3. Reproductive Sciences Program, University of Michigan Medical School, Ann Arbor, MI, USA
    • Correspondence

      David M. Aronoff, Division of Infectious Diseases, Department of Internal Medicine, University of Michigan Health System, 5510-E Medical Sciences Research Building I, 1150 West Medical Center Drive, Ann Arbor, MI 48109-5680, USA.

      E-mail: daronoff@umich.edu

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Abstract

Problem

Clostridium sordellii causes endometrial infections, but little is known regarding host defenses against this pathogen.

Method of study

We tested the hypothesis that the immunoregulatory lipid prostaglandin (PG) E2 suppresses human macrophage clearance of C. sordellii through receptor-induced increases in intracellular cyclic adenosine monophosphate (cAMP). The THP-1 macrophage cell line was used to quantify C. sordellii phagocytosis.

Results

PGE2 increased cAMP levels, activated protein kinase A (PKA), and inhibited the class A scavenger receptor-dependent phagocytosis of C. sordellii. Activation of the EP2 and EP4 receptors increased intracellular cAMP and inhibited phagocytosis, with evidence favoring a more important role for EP4 over EP2. This was supported by EP receptor expression data and the use of pharmacological receptor antagonists. In addition, the PKA isoform RI appeared to be more important than RII in mediating the suppression of ingestion of C. sordellii.

Conclusion

The endogenous lipid mediator PGE2 impairs human innate immune responses against C. sordellii.

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