title: P2X7 receptor-dependent tuning of gut epithelial responses to infection.
abstract: Infection and injury of the gut are associated with cell damage and release of molecules such as extracellular adenosine 5'-triphosphate (ATP), which is recognised by the purinergic P2X7 receptor (P2X7R). P2X7R is widely expressed in the gut by antigen-presenting cells (APCs) and epithelial cells, but the role of the P2X7R on epithelial cells is poorly understood. We investigated P2X7R in intestinal epithelium in vitro and in vivo using two model infections, Toxoplasma gondii and Trichinella spiralis. Lipopolysaccharide and ATP treatment of intestinal epithelial cells and infection with T. gondii in vitro did not promote inflammasome-associated interleukin-1β (IL-1β) or IL-18 secretion, but promoted C-C motif chemokine ligand 5 (CCL5), tumour necrosis factor-α and IL-6 production that were significantly reduced when the P2X7R was blocked. Similarly, in vivo, infection with either T. spiralis or T. gondii induced rapid upregulation of epithelial CCL5 in wild-type (wild-type (WT)) mice that was significantly reduced in P2X7R-/-littermate controls. The effects of reduced epithelial CCL5 were assayed by investigating recruitment of dendritic cells (DCs) to the epithelium. Infection induced a rapid recruitment of CD11c+CD103+DC subsets into the epithelial layer of WT mice but not P2X7R-/-mice. In vitro chemotaxis assays and bone marrow chimeras demonstrated the importance of epithelial P2X7R in DC recruitment. P2X7R signalling in epithelial cells mediates chemokine responses to promote initiation of host immunity to infection.
authors: Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.
authors: Szu-Wei
authors: SW
authors: Huang
authors: Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.
authors: Catherine
authors: C
authors: Walker
authors: Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.
authors: Joanne
authors: J
authors: Pennock
authors: Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.
authors: Kathryn
authors: K
authors: Else
authors: Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.
authors: Werner
authors: W
authors: Muller
authors: Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.
authors: Michael Jd
authors: MJ
authors: Daniels
authors: Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
authors: Carolina
authors: C
authors: Pellegrini
authors: Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.
authors: David
authors: D
authors: Brough
authors: Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.
authors: Gloria
authors: G
authors: Lopez-Castejon
authors: Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.
authors: Sheena M
authors: SM
authors: Cruickshank
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D018946:Chemokine CCL5 / Q000096:biosynthesis; D002633:Chemotaxis; D003713:Dendritic Cells / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism / Q000469:parasitology; D041981:Gastrointestinal Tract / Q000473:pathology*; D007413:Intestinal Mucosa / Q000276:immunology* / Q000469:parasitology* / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D059208:Parasite Load; D058486:Receptors, Purinergic P2X7 / Q000172:deficiency / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology; D014122:Toxoplasma; D014123:Toxoplasmosis / Q000276:immunology / Q000469:parasitology / Q000473:pathology
chemical_list: D018946:Chemokine CCL5; D058486:Receptors, Purinergic P2X7