| First Author | Brigo N | Year | 2023 |
| Journal | Cells | Volume | 12 |
| Issue | 8 | PubMed ID | 37190073 |
| Mgi Jnum | J:340993 | Mgi Id | MGI:7483195 |
| Doi | 10.3390/cells12081164 | Citation | Brigo N, et al. (2023) Timing of Interleukin-4 Stimulation of Macrophages Determines Their Anti-Microbial Activity during Infection with Salmonella enterica Serovar Typhimurium. Cells 12(8) |
| abstractText | Priming of macrophages with interferon-gamma (IFNgamma) 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(+/-)ARG1(fl/fl) (KO), Tie2Cre(-/-)ARG1(fl/fl) (WT) mice were infected with S.tm in the undifferentiated state and then stimulated with IL-4 or IFNgamma. In addition, BMDM of C57BL/6N mice were first polarised upon stimulation with IL-4 or IFNgamma 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 IFNgamma 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. |
