The In Vitro M1/M2 Polarization of Macrophages of BCG-Infected Mice

Ильин, Д. А.; Shkurupy, V. A.

doi:10.1007/s10517-020-04910-w

Cited by 5 publications

(1 citation statement)

References 8 publications

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“…This is in line with earlier studies indicating that differences in the macrophage polarisation state determine antimicrobial host responses and therefore the susceptibility and outcome of infectious diseases with various pathogens [ 3 , 4 , 5 , 6 ]. This involves the induction of the NO-generating enzyme iNOS, efficiently induced by IFNγ, and the L-arginine-depleting enzyme arginase 1 (ARG1), stimulated by IL-4 [ 4 , 5 , 6 , 8 , 41 , 42 ].…”

Section: Discussionmentioning

confidence: 99%

Timing of Interleukin-4 Stimulation of Macrophages Determines Their Anti-Microbial Activity during Infection with Salmonella enterica Serovar Typhimurium

Brigo

Neumaier

Pfeifhofer-Obermair

et al. 2023

Cells

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Priming of macrophages with interferon-gamma (IFNγ) or interleukin-4 (IL-4) leads to polarisation into pro-inflammatory or anti-inflammatory subtypes, which produce key enzymes such as inducible nitric oxide synthase (iNOS) and arginase 1 (ARG1), respectively, and in this way determine host responses to infection. Importantly, L-arginine is the substrate for both enzymes. ARG1 upregulation is associated with increased pathogen load in different infection models. However, while differentiation of macrophages with IL-4 impairs host resistance to the intracellular bacterium Salmonella enterica serovar Typhimurium (S.tm), little is known on the effects of IL-4 on unpolarised macrophages during infection. Therefore, bone-marrow-derived macrophages (BMDM) from C57BL/6N, Tie2Cre+/−ARG1fl/fl (KO), Tie2Cre−/−ARG1fl/fl (WT) mice were infected with S.tm in the undifferentiated state and then stimulated with IL-4 or IFNγ. In addition, BMDM of C57BL/6N mice were first polarised upon stimulation with IL-4 or IFNγ and then infected with S.tm. Interestingly, in contrast to polarisation of BMDM with IL-4 prior to infection, treatment of non-polarised S.tm-infected BMDM with IL-4 resulted in improved infection control whereas stimulation with IFNγ led to an increase in intracellular bacterial numbers compared to unstimulated controls. This effect of IL-4 was paralleled by decreased ARG1 levels and increased iNOS expression. Furthermore, the L-arginine pathway metabolites ornithine and polyamines were enriched in unpolarised cells infected with S.tm and stimulated with IL-4. Depletion of L-arginine reversed the protective effect of IL-4 toward infection control. Our data show that stimulation of S.tm-infected macrophages with IL-4 reduced bacterial multiplication via metabolic re-programming of L-arginine-dependent pathways.

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