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2014 ; 44
(4
): 1119-29
Nephropedia Template TP
Subramanian M
; Kini R
; Madasu M
; Ohta A
; Nowak M
; Exley M
; Sitkovsky M
; Ohta A
Eur J Immunol
2014[Apr]; 44
(4
): 1119-29
PMID24448964
show ga
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 ?-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
?-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.