The Prostaglandin E2-EP3 Receptor Axis Regulates Anaplasma phagocytophilum-Mediated NLRC4 Inflammasome Activation

Xiaowei Wang, Dana K. Shaw, Holly L. Hammond, Fayyaz S. Sutterwala, Manira Rayamajhi, Kari Ann Shirey, Darren J. Perkins, Joseph V. Bonventre, Thangam S. Velayutham, Sean M. Evans, Kyle G. Rodino, Lauren VieBrock, Karen M. Scanlon, Nicholas H. Carbonetti, Jason A. Carlyon, Edward A. Miao, Jere McBride, Michail Kotsyfakis, Joao H F Pedra

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Rickettsial agents are sensed by pattern recognition receptors but lack pathogen-associated molecular patterns commonly observed in facultative intracellular bacteria. Due to these molecular features, the order Rickettsiales can be used to uncover broader principles of bacterial immunity. Here, we used the bacterium Anaplasma phagocytophilum, the agent of human granulocytic anaplasmosis, to reveal a novel microbial surveillance system. Mechanistically, we discovered that upon A. phagocytophilum infection, cytosolic phospholipase A2 cleaves arachidonic acid from phospholipids, which is converted to the eicosanoid prostaglandin E2 (PGE2) via cyclooxygenase 2 (COX2) and the membrane associated prostaglandin E synthase-1 (mPGES-1). PGE2-EP3 receptor signaling leads to activation of the NLRC4 inflammasome and secretion of interleukin (IL)-1β and IL-18. Importantly, the receptor-interacting serine/threonine-protein kinase 2 (RIPK2) was identified as a major regulator of the immune response against A. phagocytophilum. Accordingly, mice lacking COX2 were more susceptible to A. phagocytophilum, had a defect in IL-18 secretion and exhibited splenomegaly and damage to the splenic architecture. Remarkably, Salmonella-induced NLRC4 inflammasome activation was not affected by either chemical inhibition or genetic ablation of genes associated with PGE2 biosynthesis and signaling. This divergence in immune circuitry was due to reduced levels of the PGE2-EP3 receptor during Salmonella infection when compared to A. phagocytophilum. Collectively, we reveal the existence of a functionally distinct NLRC4 inflammasome illustrated by the rickettsial agent A. phagocytophilum.

Original languageEnglish (US)
Article numbere1005803
JournalPLoS Pathogens
Volume12
Issue number8
DOIs
StatePublished - Aug 1 2016

Fingerprint

Anaplasma phagocytophilum
Inflammasomes
Dinoprostone
Interleukin-18
Receptor-Interacting Protein Serine-Threonine Kinase 2
Anaplasmosis
Cytosolic Phospholipases A2
Bacteria
Pattern Recognition Receptors
Eicosanoids
Salmonella Infections
Splenomegaly
Cyclooxygenase 2
Interleukin-1
Arachidonic Acid
Salmonella
Immunity
Phospholipids
Membranes
Infection

ASJC Scopus subject areas

  • Microbiology
  • Parasitology
  • Virology
  • Immunology
  • Genetics
  • Molecular Biology

Cite this

Wang, X., Shaw, D. K., Hammond, H. L., Sutterwala, F. S., Rayamajhi, M., Shirey, K. A., ... Pedra, J. H. F. (2016). The Prostaglandin E2-EP3 Receptor Axis Regulates Anaplasma phagocytophilum-Mediated NLRC4 Inflammasome Activation. PLoS Pathogens, 12(8), [e1005803]. https://doi.org/10.1371/journal.ppat.1005803

The Prostaglandin E2-EP3 Receptor Axis Regulates Anaplasma phagocytophilum-Mediated NLRC4 Inflammasome Activation. / Wang, Xiaowei; Shaw, Dana K.; Hammond, Holly L.; Sutterwala, Fayyaz S.; Rayamajhi, Manira; Shirey, Kari Ann; Perkins, Darren J.; Bonventre, Joseph V.; Velayutham, Thangam S.; Evans, Sean M.; Rodino, Kyle G.; VieBrock, Lauren; Scanlon, Karen M.; Carbonetti, Nicholas H.; Carlyon, Jason A.; Miao, Edward A.; McBride, Jere; Kotsyfakis, Michail; Pedra, Joao H F.

In: PLoS Pathogens, Vol. 12, No. 8, e1005803, 01.08.2016.

Research output: Contribution to journalArticle

Wang, X, Shaw, DK, Hammond, HL, Sutterwala, FS, Rayamajhi, M, Shirey, KA, Perkins, DJ, Bonventre, JV, Velayutham, TS, Evans, SM, Rodino, KG, VieBrock, L, Scanlon, KM, Carbonetti, NH, Carlyon, JA, Miao, EA, McBride, J, Kotsyfakis, M & Pedra, JHF 2016, 'The Prostaglandin E2-EP3 Receptor Axis Regulates Anaplasma phagocytophilum-Mediated NLRC4 Inflammasome Activation', PLoS Pathogens, vol. 12, no. 8, e1005803. https://doi.org/10.1371/journal.ppat.1005803
Wang, Xiaowei ; Shaw, Dana K. ; Hammond, Holly L. ; Sutterwala, Fayyaz S. ; Rayamajhi, Manira ; Shirey, Kari Ann ; Perkins, Darren J. ; Bonventre, Joseph V. ; Velayutham, Thangam S. ; Evans, Sean M. ; Rodino, Kyle G. ; VieBrock, Lauren ; Scanlon, Karen M. ; Carbonetti, Nicholas H. ; Carlyon, Jason A. ; Miao, Edward A. ; McBride, Jere ; Kotsyfakis, Michail ; Pedra, Joao H F. / The Prostaglandin E2-EP3 Receptor Axis Regulates Anaplasma phagocytophilum-Mediated NLRC4 Inflammasome Activation. In: PLoS Pathogens. 2016 ; Vol. 12, No. 8.
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AU - Rayamajhi, Manira

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