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.
Highlights
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)
ATP released from dying cells can enhance P2X7R activation[7] and trigger activation of the NLRP3 ((NLR family, pyrin domain containing 3)) inflammasome-promoting secretion of the proinflammatory cytokines interleukin-1β (IL-1β) and IL-18.4 the P2X7R is expressed by a variety of cell types including immune[4] and epithelial cells,[8] the activity of P2X7R is best described in immune cells
IL-18 was secreted at low levels by CMT-93 cells, but this response was not affected by infection or P2X7R inhibition (Figure 1e)
Summary
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). 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. As well as responding to the threat of invading pathogens, the gut must be tolerant to host microbiota Both host microbiota and pathogens express highly conserved molecular patterns that could potentially trigger host immunity, most commensal microbiota are noninvasive.[1] Further, there is physical separation of host microbiota and the epithelium in the gut because of the presence of a dense mucus layer.[1,2] a key discriminating feature of a pathogen vs a host microbiota species is that pathogens actively invade and breach the epithelial layer causing cell damage and death. P2X7R in macrophages and DCs promote phagolysosomal fusion and parasite killing in vitro.[10,11]
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