Adenosine metabolized from extracellular ATP promotes type 2 immunity through triggering A2BAR signaling in intestinal epithelial cells

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

doi:10.1016/j.celrep.2022.111150

Adenosine metabolized from extracellular ATP promotes type 2 immunity through triggering A_2BAR signaling in intestinal epithelial cells

Cell Rep. 2022 Aug 2;40(5):111150. doi: 10.1016/j.celrep.2022.111150.

Affiliations

¹ Center for Immunity and Inflammation, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, NJ 07101, USA; Department of Medicine, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, NJ 07101, USA.
² Center for Immunity and Inflammation, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, NJ 07101, USA; Department of Pathology, Immunology, and Laboratory Medicine, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, NJ 07101, USA.
³ Department of Anesthesiology, University of Texas at Houston Medical School, Houston, TX 77030, USA.
⁴ Center for Inflammation Research, Department of Anesthesia, Critical Care & Pain Medicine and Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA.
⁵ Department of Medical Sciences, University of Ferrara, Ferrara, Italy.
⁶ Department of Anesthesiology, Columbia University, New York, NY, USA. Electronic address: [email protected].
⁷ Center for Immunity and Inflammation, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, NJ 07101, USA; Department of Medicine, New Jersey Medical School, Rutgers-The State University of New Jersey, Newark, NJ 07101, USA. Electronic address: [email protected].

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 A_2B adenosine receptor (A_2BAR) on intestinal epithelial cells (IECs) plays an important role. Specific blockade of IEC A_2BAR 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: CP: Immunology; CP: Molecular biology.

Publication types

Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

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

Substances

Receptor, Adenosine A2B
Adenosine Triphosphate
Adenosine