Extracellular adenosine controls NKT‐cell‐dependent hepatitis induction. Issue 4 (19th February 2014)

• Record Type: Journal Article
• Authors: Subramanian, Meenakshi; Kini, Radhika; Madasu, Manasa; Ohta, Akiko; Nowak, Michael; Exley, Mark; Sitkovsky, Michail; Ohta, Akio
• Is Part Of: European journal of immunology. Volume 44:Issue 4(2014:Apr.)
• Page Start: 1119
• Page End: 1129
• Publication Date: 2014-02-19
• Subjects: Immunology -- Periodicals; 616.079
• DOI: 10.1002/eji.201343866
• Languages: English
• ISSNs: 0014-2980

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>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.</p> </abstract>