Abstract
Arginase 1 (ARG1) is a cytosolic enzyme that cleaves L-arginine, the substrate of inducible nitric oxide synthase (iNOS), and thereby impairs the control of various intracellular pathogens. Herein, we investigated the role of ARG1 during infection with Salmonella enterica serovar Typhimurium (S.tm). To study the impact of ARG1 on Salmonella infections in vitro, bone marrow-derived macrophages (BMDM) from C57BL/6N wild-type, ARG1-deficient Tie2Cre+/−ARG1fl/fl and NRAMPG169 C57BL/6N mice were infected with S.tm. In wild-type BMDM, ARG1 was induced by S.tm and further upregulated by the addition of interleukin (IL)-4, whereas interferon-γ had an inhibitory effect. Deletion of ARG1 did not result in a reduction in bacterial numbers. In vivo, Arg1 mRNA was upregulated in the spleen, but not in the liver of C57BL/6N mice following intraperitoneal S.tm infection. The genetic deletion of ARG1 (Tie2Cre+/−ARG1fl/fl) or its pharmacological inhibition with CB-1158 neither affected the numbers of S.tm in spleen, liver and blood nor the expression of host response genes such as iNOS, IL-6 or tumour necrosis factor (TNF). Furthermore, ARG1 was dispensable for pathogen control irrespective of the presence or absence of the phagolysosomal natural resistance-associated macrophage protein 1 (NRAMP1). Thus, unlike the detrimental function of ARG1 seen during infections with other intraphagosomal microorganisms, ARG1 did not support bacterial survival in systemic salmonellosis, indicating differential roles of arginine metabolism for host immune response and microbe persistence depending on the type of pathogen.
Highlights
Macrophages belong to the phagocytic cells of the innate immune system and represent one of the first lines of defence against invading pathogens
Representative data of technical triplicates or quadruplicates are shown for (a–c) and (e); technical duplicates are shown for (d) and (f). Having seen this principal regulation of iNos and Arg1 by cytokines and Salmonella, we studied their expression over time (3–24 h) (Figure 1e). iNos mRNA levels were strongly induced by IFNγ in both uninfected and infected macrophages (Figure 1e), which, did not translate into induction of inducible nitric oxide synthase (iNOS) protein in uninfected macrophages stimulated with IFNγ (Figure 1f)
The induction of Arginase 1 (ARG1) has been linked to an increase in tissue pathogen loads in the case of infections with Leishmania, Trypanosoma or Mycobacteria spp., whereas the inhibition or deletion of ARG1 led to improved infection control by the host [10,13,14,15,16,47]
Summary
Macrophages belong to the phagocytic cells of the innate immune system and represent one of the first lines of defence against invading pathogens. The cytosolic enzyme ARG1 is upregulated by cytokines and microbial products during infections, which usually promotes pathogen survival in macrophages by converting. Interferon gamma (IFNγ) and tumour necrosis factor (TNF), along with bacterial lipopolysaccharides, are potent inducers of iNOS [7,8,9]. Part of the host protective effects of TNF and IFNγ can be traced back to their inhibitory effect on the expression of ARG1, thereby promoting NO formation for antimicrobial host defence [10,11]. TNF and IFNγ have been demonstrated to inhibit the transcription of ARG1 by hindering the IL-4-induced chromatin remodelling [10,11,12]. In bone marrow-derived macrophages (BMDM) the simultaneous addition of TNF and IL-4 resulted in downregulation of Arg mRNA and protein expression via TNF-mediated epigenetic inhibition of ARG1 induction by IL-4
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