Rationale: Sepsis induces a sustained immune dysfunction responsible for poor outcome and nosocomial infections. Myeloid-derived suppressor cells (MDSCs) described in cancer and inflammatory processes may be involved in sepsis-induced immune suppression but their clinical impact remains poorly defined. Objectives: To clarify phenotype, suppressive activity, origin, and clinical impact of MDSCs in septic patients. Methods: Peripheral blood transcriptomic analysis was performed on 29 septic patients and 15 healthy donors. A second cohort of 94 consecutive septic patients, 11 severity-matched intensive care patients and 67 healthy donors was prospectively enrolled for flow cytometry and functional experiments. Measurements and Main Results: Genes involved in MDSC suppressive functions, including S100A12, S100A9, MMP8 and ARG1, were upregulated in the peripheral blood of septic patients. CD14^posHLA-DR^low/neg monocytic (M)-MDSCs were expanded in intensive care septic and non-septic patients and CD14^negCD15^pos low-density granulocytes/ granulocytic (G)-MDSCs were more specifically expanded in septic patients (p<.001). Plasma levels of MDSC mediators S100A8/A9, S100A12, and Arginase 1 were significantly increased. In vitro, CD14^pos- and CD15^pos-cell depletion increased T-cell proliferation in septic patients. G-MDSCs, made of immature and mature granulocytes expressing high levels of degranulation markers, were specifically responsible for arginase 1 activity. High initial levels of G-MDSCs, arginase 1, and S100A12 but not M-MDSCs were associated with subsequent occurrence of nosocomial infections. Conclusions: M-MDSCs and G-MDSCs strongly contribute to T-cell dysfunction in septic patients. More specifically, G-MDSCs producing arginase 1 are associated with a higher incidence of nosocomial infections and appear to be major actors of sepsis-induced immune suppression.

Ornithine δ-aminotransferase (OAT, E.C. 2.6.1.13) catalyzes the transfer of the δ-amino group from ornithine (Orn) to α-ketoglutarate (aKG), yielding glutamate-5-semialdehyde and glutamate (Glu), and vice versa. In mammals, OAT is a mitochondrial enzyme, mainly located in the liver, intestine, brain, and kidney. In general, OAT serves to form glutamate from ornithine, with the notable exception of the intestine, where citrulline (Cit) or arginine (Arg) are end products. Its main function is to control the production of signaling molecules and mediators, such as Glu itself, Cit, GABA, and aliphatic polyamines. It is also involved in proline (Pro) synthesis. Deficiency in OAT causes gyrate atrophy, a rare but serious inherited disease, a further measure of the importance of this enzyme.

Arginine (ARG) and its precursor citrulline (CIT) are popular dietary supplements, especially for the elderly. However, age-related reductions in lean body mass and alterations in organ functions could change their bioavailability. Pharmacokinetics and tolerance to amino acid (AA) loads are poorly documented in elderly subjects. The objective here was to characterise the plasma kinetics of CIT and ARG in a single-dosing study design. Eight fasting elderly men underwent two separate isomolar oral loading tests (10 g of CIT or 9·94 g of ARG). Blood was withdrawn over an 8-h period to measure plasma AA concentrations. Only CIT, ornithine and ARG plasma concentrations were changed. Volume of distribution was not dependent on AA administered. Conversely, parameters related to ARG kinetics were strongly dependent on AA administered: after ARG load, elimination was higher (ARG>CIT; P=0·041) and admission period+time at peak concentration was lower (ARG<CIT; P=0·033), and the combination of both phenomena results in a marked increase in ARG availability when CIT was administered (ARG<CIT; P=0·033) compared with ARG administration itself. In conclusion, a single CIT administration in the elderly is safe and well tolerated, and CIT proves to be a better in vivo ARG precursor than ARG itself in healthy elderly subjects.