Stat 6-Dependent Induction of Myeloid Derived Suppressor Cells After Physical Injury Regulates Nitric Oxide Response to Endotoxin

In Brief Objective: To delineate the role of T-helper 2 (Th2) cytokines in the induction of trauma induced myeloid suppressor cells (TIMSC) and the regulation of nitric oxide production. Background: Trauma induces myeloid cells that express CD11b+/Gr1+ and arginase 1 and exhibit an immune suppressing activity. This article explores the mechanisms that induce TIMSC and the effects on nitric oxide production in response to endotoxin. Methods: TIMSC were studied in response to Th2 cytokines and a subsequent challenge to endotoxin. The role of Th2 cytokines was studied in STAT6−/− mice. Accumulation of TIMSC in spleens was studied using flow cytometry and immunhistochemistry. Plasma was recovered to measure accumulation of nitric oxide metabolites. Results: TIMSC accumulated in the spleen of injured mice and were particularly sensitive to IL-4 and IL-13 with large inductions of arginase activity. Significant blunting in both the accumulation of TIMSC in the spleen and induction of arginase 1 was observed in STAT6−/− mice after physical injury. Accumulation of nitric oxide metabolites to endotoxin was observed in STAT6−/− mice. Conclusion: This study shows that induction of CD11b+/Gr1+ cells after physical injury play an essential role in the regulation of nitric oxide production after a septic challenge. The accumulation and induction of arginase 1 in TIMSC is Th2 cytokine dependent. To our knowledge, the role of TIMSC in the regulation of nitric oxide is a novel finding. This observation adds to the possibility that TIMSC could play an important role in immunosuppression observed after physical injury. Trauma induced myeloid suppressor cells (TIMSC) deplete arginine after trauma through an increased metabolism by Arginase 1. Accumulation and activation of TIMSC is, at least in part, Th2 cytokines dependent. Through arginine deficiency TIMSC may regulate accumulation of nitric oxide products in response to endotoxin.