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

DSpace/Manakin Repository

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

Citable link to this page

 

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

Note: Order does not necessarily reflect citation order of authors.

Citation: Wang, X., D. K. Shaw, H. L. Hammond, F. S. Sutterwala, M. Rayamajhi, K. A. Shirey, D. J. Perkins, et al. 2016. “The Prostaglandin E2-EP3 Receptor Axis Regulates Anaplasma phagocytophilum-Mediated NLRC4 Inflammasome Activation.” PLoS Pathogens 12 (8): e1005803. doi:10.1371/journal.ppat.1005803. http://dx.doi.org/10.1371/journal.ppat.1005803.
Full Text & Related Files:
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.
Published Version: doi:10.1371/journal.ppat.1005803
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4970705/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:29002472
Downloads of this work:

Show full Dublin Core record

This item appears in the following Collection(s)

 
 

Search DASH


Advanced Search
 
 

Submitters