Extracellular adenosine controls NKT-cell-dependent hepatitis induction.
Extracellular adenosine regulates inflammatory responses via the A2A adenosine receptor (A2AR). A2AR deficiency results in much exaggerated acute hepatitis, indicating nonredundancy of adenosine-A2AR pathway in inhibiting immune activation. To identify a critical target of immunoregulatory effect of extracellular adenosine, we focused on NKT cells, which play an indispensable role in hepatitis. An A2AR agonist abolished NKT-cell-dependent induction of acute hepatitis by concanavalin A (Con A) or α-galactosylceramide in mice, corresponding to downregulation of activation markers and cytokines in NKT cells and of NK-cell co-activation. These results show that A2AR signaling can downregulate NKT-cell activation and suppress NKT-cell-triggered inflammatory responses. Next, we hypothesized that NKT cells might be under physiological control of the adenosine-A2AR pathway. Indeed, both Con A and α-galactosylceramide induced more severe hepatitis in A2AR-deficient mice than in WT controls. Transfer of A2AR-deficient NKT cells into A2AR-expressing recipients resulted in exaggeration of Con A-induced liver damage, suggesting that NKT-cell activation is controlled by endogenous adenosine via A2AR, and this physiological regulatory mechanism of NKT cells is critical in the control of tissue-damaging inflammation. The current study suggests the possibility to manipulate NKT-cell activity in inflammatory disorders through intervention to the adenosine-A2AR pathway.
New England Inflammation and Tissue Protection Institute, Northeastern University, Boston, MA, USA.
Meenakshi
M
Subramanian
Radhika
R
Kini
Manasa
M
Madasu
Akiko
A
Ohta
Michael
M
Nowak
Mark
M
Exley
Michail
M
Sitkovsky
Akio
A
Ohta
D000241:Adenosine / Q000031:analogs & derivatives / Q000276:immunology* / Q000494:pharmacology; D058908:Adenosine A2 Receptor Agonists / Q000276:immunology / Q000494:pharmacology; D058917:Adenosine A2 Receptor Antagonists / Q000276:immunology / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D003208:Concanavalin A; D005434:Flow Cytometry; D005699:Galactosylceramides; D006520:Hepatitis, Animal / Q000139:chemically induced / Q000235:genetics / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D008099:Liver / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055611:Natural Killer T-Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D010627:Phenethylamines / Q000276:immunology / Q000494:pharmacology; D043705:Receptor, Adenosine A2A / Q000276:immunology* / Q000378:metabolism; D014227:Triazines / Q000276:immunology / Q000494:pharmacology; D014230:Triazoles / Q000276:immunology / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism
D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D005699:Galactosylceramides; D010627:Phenethylamines; D043705:Receptor, Adenosine A2A; D014227:Triazines; D014230:Triazoles; D014409:Tumor Necrosis Factor-alpha; C097270:ZM 241385; C493154:alpha-galactosylceramide; D003208:Concanavalin A; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D007371:Interferon-gamma; D000241:Adenosine
A2A adenosine receptor; Adenosine; Hepatitis; Immunoregulation; NKT cell