Abstract
L-amino acid oxidases (LAAO) are flavoproteins that catalyze the oxidative deamination of L-amino acids to a keto-acid along with the production of H2O2 and ammonia. Interleukin 4 induced gene 1 (IL4I1) is a secreted LAAO expressed by macrophages and dendritic cells stimulated by microbial derived products or interferons, which is endowed with immunoregulatory properties. It is the first LAAO described in mammalian innate immune cells. In this work, we show that this enzyme blocks the in vitro and in vivo growth of Gram negative and Gram positive bacteria. This antibiotic effect is primarily mediated by H2O2 production but is amplified by basification of the medium due to the accumulation of ammonia. The depletion of phenylalanine (the primary amino acid catabolized by IL4I1) may also participate in the in vivo inhibition of staphylococci growth. Thus, IL4I1 plays a distinct role compared to other antibacterial enzymes produced by mononuclear phagocytes.
Highlights
L-amino acid oxidases (LAAO) are homodimeric flavoproteins that catalyse the stereospecific deamination of L-amino acid substrates to a keto-acid along with the production of H2O2 and ammonia
We tested the antibacterial effect of conditioned media from Interleukin 4 induced gene 1 (IL4I1)-expressing THP1 monocytes on four bacterial strains, representative of Gram-negative bacilli and Gram-positive cocci, i.e. Escherichia coli DH5a (E. coli), an Escherichia coli strain auxotrophic for Phe (B2599) and 2 Staphylococcus strains, a methicillin-susceptible Staphylococcus aureus (MSSA) and a coagulasenegative Staphylococcus (CNS)
IL4I1-mediated NH3 production could not be detected in THP1 and THP1-IL4I1 conditioned media, because of a strong basal level mainly due to glutamine instability, we confirmed the production of ammonia in Phe-containing conditioned PBS (Figure S1)
Summary
L-amino acid oxidases (LAAO) are homodimeric flavoproteins that catalyse the stereospecific deamination of L-amino acid substrates to a keto-acid along with the production of H2O2 and ammonia These enzymes are widely expressed in many different organisms from prokaryotes to metazoans, of which snake venom LAAO being the most studied. Venom LAAO have been suggested to act as toxins involved in the induction of apoptosis in a variety of different mammalian cell types. They are associated with the dysfunction of platelet aggregation [1]. At physiological pH and temperature, IL4I1 degrades the essential amino acid phenylalanine (Phe), producing phenylpyruvate, H2O2 and ammonia By this activity, IL4I1 depletes the microenvironment of an essential amino acid and induces the accumulation of potentially toxic products. We have demonstrated that IL4I1 is involved in the control of the adaptative immune response via its enzymatic activity [3,4]
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