The Prostaglandin E2-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...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2016-08-01
|
| Series: | PLoS Pathogens |
| Online Access: | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1005803&type=printable |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849717066247962624 |
|---|---|
| author | 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 W McBride Michail Kotsyfakis Joao H F Pedra |
| author_facet | 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 W McBride Michail Kotsyfakis Joao H F Pedra |
| author_sort | Xiaowei Wang |
| collection | DOAJ |
| 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 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. |
| format | Article |
| id | doaj-art-130f8b62410e47cdafb35a596bcc86c1 |
| institution | DOAJ |
| issn | 1553-7366 1553-7374 |
| language | English |
| publishDate | 2016-08-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj-art-130f8b62410e47cdafb35a596bcc86c12025-08-20T03:12:47ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742016-08-01128e100580310.1371/journal.ppat.1005803The Prostaglandin E2-EP3 Receptor Axis Regulates Anaplasma phagocytophilum-Mediated NLRC4 Inflammasome Activation.Xiaowei WangDana K ShawHolly L HammondFayyaz S SutterwalaManira RayamajhiKari Ann ShireyDarren J PerkinsJoseph V BonventreThangam S VelayuthamSean M EvansKyle G RodinoLauren VieBrockKaren M ScanlonNicholas H CarbonettiJason A CarlyonEdward A MiaoJere W McBrideMichail KotsyfakisJoao H F PedraRickettsial 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.https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1005803&type=printable |
| spellingShingle | 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 W McBride Michail Kotsyfakis Joao H F Pedra The Prostaglandin E2-EP3 Receptor Axis Regulates Anaplasma phagocytophilum-Mediated NLRC4 Inflammasome Activation. PLoS Pathogens |
| title | The Prostaglandin E2-EP3 Receptor Axis Regulates Anaplasma phagocytophilum-Mediated NLRC4 Inflammasome Activation. |
| title_full | The Prostaglandin E2-EP3 Receptor Axis Regulates Anaplasma phagocytophilum-Mediated NLRC4 Inflammasome Activation. |
| title_fullStr | The Prostaglandin E2-EP3 Receptor Axis Regulates Anaplasma phagocytophilum-Mediated NLRC4 Inflammasome Activation. |
| title_full_unstemmed | The Prostaglandin E2-EP3 Receptor Axis Regulates Anaplasma phagocytophilum-Mediated NLRC4 Inflammasome Activation. |
| title_short | The Prostaglandin E2-EP3 Receptor Axis Regulates Anaplasma phagocytophilum-Mediated NLRC4 Inflammasome Activation. |
| title_sort | prostaglandin e2 ep3 receptor axis regulates anaplasma phagocytophilum mediated nlrc4 inflammasome activation |
| url | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1005803&type=printable |
| work_keys_str_mv | AT xiaoweiwang theprostaglandine2ep3receptoraxisregulatesanaplasmaphagocytophilummediatednlrc4inflammasomeactivation AT danakshaw theprostaglandine2ep3receptoraxisregulatesanaplasmaphagocytophilummediatednlrc4inflammasomeactivation AT hollylhammond theprostaglandine2ep3receptoraxisregulatesanaplasmaphagocytophilummediatednlrc4inflammasomeactivation AT fayyazssutterwala theprostaglandine2ep3receptoraxisregulatesanaplasmaphagocytophilummediatednlrc4inflammasomeactivation AT manirarayamajhi theprostaglandine2ep3receptoraxisregulatesanaplasmaphagocytophilummediatednlrc4inflammasomeactivation AT kariannshirey theprostaglandine2ep3receptoraxisregulatesanaplasmaphagocytophilummediatednlrc4inflammasomeactivation AT darrenjperkins theprostaglandine2ep3receptoraxisregulatesanaplasmaphagocytophilummediatednlrc4inflammasomeactivation AT josephvbonventre theprostaglandine2ep3receptoraxisregulatesanaplasmaphagocytophilummediatednlrc4inflammasomeactivation AT thangamsvelayutham theprostaglandine2ep3receptoraxisregulatesanaplasmaphagocytophilummediatednlrc4inflammasomeactivation AT seanmevans theprostaglandine2ep3receptoraxisregulatesanaplasmaphagocytophilummediatednlrc4inflammasomeactivation AT kylegrodino theprostaglandine2ep3receptoraxisregulatesanaplasmaphagocytophilummediatednlrc4inflammasomeactivation AT laurenviebrock theprostaglandine2ep3receptoraxisregulatesanaplasmaphagocytophilummediatednlrc4inflammasomeactivation AT karenmscanlon theprostaglandine2ep3receptoraxisregulatesanaplasmaphagocytophilummediatednlrc4inflammasomeactivation AT nicholashcarbonetti theprostaglandine2ep3receptoraxisregulatesanaplasmaphagocytophilummediatednlrc4inflammasomeactivation AT jasonacarlyon theprostaglandine2ep3receptoraxisregulatesanaplasmaphagocytophilummediatednlrc4inflammasomeactivation AT edwardamiao theprostaglandine2ep3receptoraxisregulatesanaplasmaphagocytophilummediatednlrc4inflammasomeactivation AT jerewmcbride theprostaglandine2ep3receptoraxisregulatesanaplasmaphagocytophilummediatednlrc4inflammasomeactivation AT michailkotsyfakis theprostaglandine2ep3receptoraxisregulatesanaplasmaphagocytophilummediatednlrc4inflammasomeactivation AT joaohfpedra theprostaglandine2ep3receptoraxisregulatesanaplasmaphagocytophilummediatednlrc4inflammasomeactivation AT xiaoweiwang prostaglandine2ep3receptoraxisregulatesanaplasmaphagocytophilummediatednlrc4inflammasomeactivation AT danakshaw prostaglandine2ep3receptoraxisregulatesanaplasmaphagocytophilummediatednlrc4inflammasomeactivation AT hollylhammond prostaglandine2ep3receptoraxisregulatesanaplasmaphagocytophilummediatednlrc4inflammasomeactivation AT fayyazssutterwala prostaglandine2ep3receptoraxisregulatesanaplasmaphagocytophilummediatednlrc4inflammasomeactivation AT manirarayamajhi prostaglandine2ep3receptoraxisregulatesanaplasmaphagocytophilummediatednlrc4inflammasomeactivation AT kariannshirey prostaglandine2ep3receptoraxisregulatesanaplasmaphagocytophilummediatednlrc4inflammasomeactivation AT darrenjperkins prostaglandine2ep3receptoraxisregulatesanaplasmaphagocytophilummediatednlrc4inflammasomeactivation AT josephvbonventre prostaglandine2ep3receptoraxisregulatesanaplasmaphagocytophilummediatednlrc4inflammasomeactivation AT thangamsvelayutham prostaglandine2ep3receptoraxisregulatesanaplasmaphagocytophilummediatednlrc4inflammasomeactivation AT seanmevans prostaglandine2ep3receptoraxisregulatesanaplasmaphagocytophilummediatednlrc4inflammasomeactivation AT kylegrodino prostaglandine2ep3receptoraxisregulatesanaplasmaphagocytophilummediatednlrc4inflammasomeactivation AT laurenviebrock prostaglandine2ep3receptoraxisregulatesanaplasmaphagocytophilummediatednlrc4inflammasomeactivation AT karenmscanlon prostaglandine2ep3receptoraxisregulatesanaplasmaphagocytophilummediatednlrc4inflammasomeactivation AT nicholashcarbonetti prostaglandine2ep3receptoraxisregulatesanaplasmaphagocytophilummediatednlrc4inflammasomeactivation AT jasonacarlyon prostaglandine2ep3receptoraxisregulatesanaplasmaphagocytophilummediatednlrc4inflammasomeactivation AT edwardamiao prostaglandine2ep3receptoraxisregulatesanaplasmaphagocytophilummediatednlrc4inflammasomeactivation AT jerewmcbride prostaglandine2ep3receptoraxisregulatesanaplasmaphagocytophilummediatednlrc4inflammasomeactivation AT michailkotsyfakis prostaglandine2ep3receptoraxisregulatesanaplasmaphagocytophilummediatednlrc4inflammasomeactivation AT joaohfpedra prostaglandine2ep3receptoraxisregulatesanaplasmaphagocytophilummediatednlrc4inflammasomeactivation |