Cytokine-Mediated Regulation of ARG1 in Macrophages and Its Impact on the Control of Salmonella enterica Serovar Typhimurium Infection

Cells

Christine Fischer¹  Verena Petzer¹  Günter Weiss¹  Lara Valente De Souza¹  Richard Hilbe¹  Sylvia Berger¹  Egon Demetz¹  Piotr Tymoszuk¹  Laura von Raffay¹  Sabine Engl¹  Natascha Brigo¹  Stefanie Dichtl¹  Markus Seifert¹  Christa Pfeifhofer-Obermair¹  Marina Barros-Pinkelnig¹  Ulrike Schleicher²  Christian Bogdan² 

[1] Department of Internal Medicine II, Medical University of Innsbruck, Anichstraße 35, 6020 Innsbruck, Austria;Mikrobiologisches Institut—Klinische Mikrobiologie, Immunologie, und Hygiene, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Universitätsklinikum Erlangen, Wasserturmstraße 3/5, 91054 Erlangen, Germany;

关键词: arginase 1;    inducible nitric oxide synthase;    Salmonella enterica serovar Typhimurium;    macrophages;    intracellular bacteria;   

DOI  :  10.3390/cells10071823

来源: DOAJ

【 摘 要 】

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^+/−ARG1^fl/fl and NRAMP^G169 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^+/−ARG1^fl/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.

【 授权许可】

Unknown