Monocyte dimethylarginine dimethylaminohydrolase 2 is regulated by pathological stress and plays a critical role in the immune response to sepsis

Abstract

Background: Asymmetric dimethylarginine (ADMA) is an endogenous competitive inhibitor of nitric oxide synthase (NOS) and regulates the synthesis of nitric oxide (NO) in vivo. ADMA is metabolised by the enzymes dimethylarginine dimethylaminohydrolase 1 and 2 (DDAH 1 and 2), which have differing tissue distributions, with DDAH2 the only isoform found in immune cells. These studies tested the hypothesis that DDAH2 plays an important role in regulating the immune response to infection by modulating ADMA concentrations. Methods: In order to test this hypothesis, a series of experiments explored the regulation of murine and human monocyte DDAH2 in response to pathophysiological stressors. The impact of global and macrophage-specific DDAH2 knockout on the haemodynamic and immune response to sepsis and the resulting association with mortality was determined using transgenic animal models. Finally, the role of DDAH2 in human septic shock was determined by analysing plasma and DNA from patients enrolled in a randomised controlled trial of vasopressor therapy. Results: In isolated monocytes, DDAH2 was found to be regulated by both Interferon-γ and hypoxia, leading to reduced intracellular ADMA concentrations and exaggerated NO synthesis by immune cells. Both global and macrophage-specific knockout of DDAH2 led to significant impairment of immune cell function and increased mortality following caecal ligation and puncture in animal models. Increased plasma ADMA and SDMA levels were shown to be associated with risk of death in 215 patients with septic shock. However, when data were corrected for methylarginine clearance, ADMA was also found to play a protective role. In this population, the DDAH2 single nucleotide polymorphism rs805305 was associated with improved survival and increased ADMA:SDMA ratio. Conclusions: Considered as a whole, these data demonstrate that DDAH2 plays an important role in regulating the immune response to sepsis and the risk of death in human septic shock.