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.

Epithelial extracellular ATP: an initiator of immunity to parasitic infections

“…Uncontrolled rupture of cells releases various damage‐associated molecular patterns (DAMPs), which are indicators of cellular damage to surrounding cells. One common DAMP, extracellular ATP, activates a member of the P2X family, P2X7R, after reaching high concentrations in the extracellular compartment 1 . Subsequently, various cellular events, including cytokine production, chemokine production and cell death, are induced, ultimately leading to inflammation 5 .…”

“…Previous studies have illustrated P2X7R's pro‐inflammatory role; 13 however, the production of CCL5 through P2X7R on IECs was found to be independent of the inflammasome. Huang et al 1 found there to be no change in IL‐1β or IL‐18 expression post infection 1 …”

“…P2X7R fulfills various critical functions on multiple different cell types. Huang et al 1 outline an essential role performed by this versatile protein. Upon activation, P2X7R is capable of triggering the inflammasome through stimulation of caspases and promotes inflammation by releasing reactive oxygen and nitrogen intermediates 13 .…”

“…In this issue of ICB, Huang et al 1 illustrate the importance of IECs acting as parasitic sensors in the early infections of both Toxoplasma gondii and Trichinella spiralis in the small intestine. Using both in vitro and in vivo models, Huang et al 1 define the role of the epithelial-associated purinergic P2X7 receptor (P2X7R) in protection against parasitic infection via orchestration of infectious immunity mediated by CD103 + CD11b + dendritic cells (DCs) ( Figure 1). Notably, the signals involved in the process were independent of the inflammasome and lead to the production of the chemokine, CCL5.…”

“…Notably, the signals involved in the process were independent of the inflammasome and lead to the production of the chemokine, CCL5. 1 T. gondii and T. spiralis are obligate intracellular parasites that infect the small intestine in a diverse number of hosts, occasionally causing serious disease in humans. 2,3 In particular, T. gondii is the second leading cause of death due to foodborne illness in the United States.…”