Adenosine Metabolized From Extracellular ATP Promotes Type 2 Immunity Through Triggering A2BAR Signaling in Intestinal Epithelial Cells

Authors

Darine W El-Naccache
Fei Chen
Mark J Palma
Alexander Lemenze
Matthew A Fischer
Wenhui Wu
Pankaj K Mishra
Holger K Eltzschig
Simon C Robson
Francesco Di Virgilio
George S Yap
Karen L Edelblum
György Haskó
William C Gause

Publication Date

8-2-2022

Journal

Cell Reports

Abstract

Intestinal nematode parasites can cross the epithelial barrier, causing tissue damage and release of danger-associated molecular patterns (DAMPs) that may promote host protective type 2 immunity. We investigate whether adenosine binding to the A2B adenosine receptor (A2BAR) on intestinal epithelial cells (IECs) plays an important role. Specific blockade of IEC A2BAR inhibits the host protective memory response to the enteric helminth, Heligmosomoides polygyrus bakeri (Hpb), including disruption of granuloma development at the host-parasite interface. Memory T cell development is blocked during the primary response, and transcriptional analyses reveal profound impairment of IEC activation. Extracellular ATP is visualized 24 h after inoculation and is shown in CD39-deficient mice to be critical for the adenosine production mediating the initiation of type 2 immunity. Our studies indicate a potent adenosine-mediated IEC pathway that, along with the tuft cell circuit, is critical for the activation of type 2 immunity.

Keywords

Adenosine, Adenosine Triphosphate, Animals, Epithelial Cells, Mice, Mice, Inbred C57BL, Mice, Knockout, Receptor, Adenosine A2B