Journal
ANNALS OF SURGERY
Volume 259, Issue 1, Pages 171-178Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/SLA.0b013e31828611f8
Keywords
arginase; arginine; immune dysfunction; MDSC; myeloid-derived suppressor cells; physical injury; surgery; trauma
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Funding
- National Institute of Health [R01-GM065914, R01-GM57384]
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Objective: To explore the hypothesis that decreased arginine availability by myeloid-derived suppressor cells (MDSCs) is a cause of T-cell dysfunction after physical injury (PI). Background: Arginine is an essential amino acid for normal T-cell function whose availability becomes limited after PI. MDSCs expressing arginase 1 are induced by PI. T-cell dysfunction after PI seems to increase the risk of infection but the mechanisms that cause it are unclear. Methods: PI was created using a standard laparotomy model. Phenotypical and functional alterations in T cells were evaluated in vivo. MDSCs expressing arginase 1 were measured by flow cytometry. Infection after PI was created by intraperitoneal injection of Listeria monocytogenes. N-Hydroxy-Nor-l-arginine (Nor-NOHA) was used as an arginase inhibitor. The effect of arginine depletion on T-cell function and susceptibility to infection was assessed through adoptive transfer of MDSC or injection of arginase into noninjured mice. Results: PI caused a decrease in intracellular arginine in T cells, loss of the T-cell receptor (TCR) CD3- chain, inhibition of in vivo T-cell proliferation, memory, and cytotoxicity. PI exponentially increased bacterial growth and mortality to L. monocytogenes. T-cell dysfunction and increased infection were reversed by arginase inhibitor Nor-NOHA but were reproduced by adoptively transferring MDSC or injecting arginase 1 to noninjured mice. Conclusions: Arginine availability is decreased after PI coinciding with an induction of MDSC expressing arginase 1. Decreased arginine may inhibit T-cell function and increase susceptibility to infection after injury.
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