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CD73 + regulatory T cells contribute to adenosine‐mediated resolution of acute lung injury
Author(s) -
Ehrentraut Heidi,
Clambey Eric T.,
McNamee Eoin N.,
Brodsky Kelley S.,
Ehrentraut Stefan F.,
Poth Jens M.,
Riegel Ann K.,
Westrich Joseph A.,
Colgan Sean P.,
Eltzschig Holger K.
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.12-225201
Subject(s) - adenosine , adoptive cell transfer , adenosine deaminase , extracellular , inflammation , immunology , medicine , adenosine a2b receptor , pharmacology , adenosine receptor , t cell , microbiology and biotechnology , immune system , biology , receptor , agonist
Acute lung injury (ALI) is characterized by alveolar injury and uncontrolled inflammation. Since most cases of ALI resolve spontaneously, understanding the endogenous mechanisms that promote ALI resolution is important to developing effective therapies. Previous studies have implicated extracellular adenosine signaling in tissue adaptation and wound healing. Therefore, we hypothesized a functional contribution for the endogenous production of adenosine during ALI resolution. As a model, we administered intratracheal LPS and observed peak lung injury at 3 d, with resolution by d 14. Treatment with pegylated adenosine‐deaminase to enhance extracellular adenosine breakdown revealed impaired ALI resolution. Similarly, genetic deletion of cd73 , the pacemaker for extracellular adenosine generation, was associated with increased mortality (0% wild‐type and 40% in cd73 –/– mice; P <0.05) and failure to resolve ALI adequately. Studies of inflammatory cell trafficking into the lungs during ALI resolution revealed that regulatory T cells (Tregs) express the highest levels of CD73. While Treg numbers in cd73 –/– mice were similar to controls, cd73 ‐deficient Tregs had attenuated immunosuppressive functions. Moreover, adoptive transfer of cd73 ‐deficient Tregs into Rag –/– mice emulated the observed phenotype in cd73 –/– mice, while transfer of wild‐type Tregs was associated with normal ALI resolution. Together, these studies implicate CD73‐dependent adenosine generation in Tregs in promoting ALI resolution.—Ehrentraut, H., Clambey, E. T., McNamee, E. N., Brodsky, K. S., Ehrentraut, S. F., Poth, J. M., Riegel, A. K., Westrich, J. A., Colgan, S. P., Eltzschig, H. K. CD73 + regulatory T cells contribute to adenosine‐mediated resolution of acute lung injury. FASEB J. 27, 2207–2219 (2013). www.fasebj.org