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The Prostaglandin E(2)-EP3 Receptor Axis Regulates Anaplasma phagocytophilum-Mediated NLRC4 Inflammasome Activation

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 u...

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Autores principales: 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 W., Kotsyfakis, Michail, Pedra, Joao H. F.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4970705/
https://www.ncbi.nlm.nih.gov/pubmed/27482714
http://dx.doi.org/10.1371/journal.ppat.1005803
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author 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 W.
Kotsyfakis, Michail
Pedra, Joao H. F.
author_facet 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 W.
Kotsyfakis, Michail
Pedra, Joao H. F.
author_sort Wang, Xiaowei
collection PubMed
description 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 A(2) cleaves arachidonic acid from phospholipids, which is converted to the eicosanoid prostaglandin E(2) (PGE(2)) via cyclooxygenase 2 (COX2) and the membrane associated prostaglandin E synthase-1 (mPGES-1). PGE(2)-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 PGE(2) biosynthesis and signaling. This divergence in immune circuitry was due to reduced levels of the PGE(2)-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.
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spelling pubmed-49707052016-08-18 The Prostaglandin E(2)-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 W. Kotsyfakis, Michail Pedra, Joao H. F. PLoS Pathog Research Article 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 A(2) cleaves arachidonic acid from phospholipids, which is converted to the eicosanoid prostaglandin E(2) (PGE(2)) via cyclooxygenase 2 (COX2) and the membrane associated prostaglandin E synthase-1 (mPGES-1). PGE(2)-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 PGE(2) biosynthesis and signaling. This divergence in immune circuitry was due to reduced levels of the PGE(2)-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. Public Library of Science 2016-08-02 /pmc/articles/PMC4970705/ /pubmed/27482714 http://dx.doi.org/10.1371/journal.ppat.1005803 Text en © 2016 Wang et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
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 W.
Kotsyfakis, Michail
Pedra, Joao H. F.
The Prostaglandin E(2)-EP3 Receptor Axis Regulates Anaplasma phagocytophilum-Mediated NLRC4 Inflammasome Activation
title The Prostaglandin E(2)-EP3 Receptor Axis Regulates Anaplasma phagocytophilum-Mediated NLRC4 Inflammasome Activation
title_full The Prostaglandin E(2)-EP3 Receptor Axis Regulates Anaplasma phagocytophilum-Mediated NLRC4 Inflammasome Activation
title_fullStr The Prostaglandin E(2)-EP3 Receptor Axis Regulates Anaplasma phagocytophilum-Mediated NLRC4 Inflammasome Activation
title_full_unstemmed The Prostaglandin E(2)-EP3 Receptor Axis Regulates Anaplasma phagocytophilum-Mediated NLRC4 Inflammasome Activation
title_short The Prostaglandin E(2)-EP3 Receptor Axis Regulates Anaplasma phagocytophilum-Mediated NLRC4 Inflammasome Activation
title_sort prostaglandin e(2)-ep3 receptor axis regulates anaplasma phagocytophilum-mediated nlrc4 inflammasome activation
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4970705/
https://www.ncbi.nlm.nih.gov/pubmed/27482714
http://dx.doi.org/10.1371/journal.ppat.1005803
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