PMID- 37190073
OWN - NLM
STAT- MEDLINE
DCOM- 20230517
LR  - 20240501
IS  - 2073-4409 (Electronic)
IS  - 2073-4409 (Linking)
VI  - 12
IP  - 8
DP  - 2023 Apr 14
TI  - Timing of Interleukin-4 Stimulation of Macrophages Determines Their 
      Anti-Microbial Activity during Infection with Salmonella enterica Serovar 
      Typhimurium.
LID - 10.3390/cells12081164 [doi]
LID - 1164
AB  - 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.
FAU - Brigo, Natascha
AU  - Brigo N
AD  - Department of Internal Medicine II, Medical University of Innsbruck, Anichstrasse 
      35, 6020 Innsbruck, Austria.
FAU - Neumaier, Emely
AU  - Neumaier E
AD  - Department of Internal Medicine II, Medical University of Innsbruck, Anichstrasse 
      35, 6020 Innsbruck, Austria.
FAU - Pfeifhofer-Obermair, Christa
AU  - Pfeifhofer-Obermair C
AD  - Department of Internal Medicine II, Medical University of Innsbruck, Anichstrasse 
      35, 6020 Innsbruck, Austria.
FAU - Grubwieser, Philipp
AU  - Grubwieser P
AUID- ORCID: 0000-0001-6233-8910
AD  - Department of Internal Medicine II, Medical University of Innsbruck, Anichstrasse 
      35, 6020 Innsbruck, Austria.
FAU - Engl, Sabine
AU  - Engl S
AD  - Department of Internal Medicine II, Medical University of Innsbruck, Anichstrasse 
      35, 6020 Innsbruck, Austria.
FAU - Berger, Sylvia
AU  - Berger S
AD  - Department of Internal Medicine II, Medical University of Innsbruck, Anichstrasse 
      35, 6020 Innsbruck, Austria.
FAU - Seifert, Markus
AU  - Seifert M
AD  - Department of Internal Medicine II, Medical University of Innsbruck, Anichstrasse 
      35, 6020 Innsbruck, Austria.
AD  - Christian Doppler Laboratory for Iron Metabolism and Anemia Research, Medical 
      University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria.
FAU - Reinstadler, Vera
AU  - Reinstadler V
AUID- ORCID: 0000-0003-3706-2910
AD  - Institute of Legal Medicine and Core Facility Metabolomics, Medical University of 
      Innsbruck, Muellerstrasse 44, 6020 Innsbruck, Austria.
FAU - Oberacher, Herbert
AU  - Oberacher H
AUID- ORCID: 0000-0002-0963-8268
AD  - Institute of Legal Medicine and Core Facility Metabolomics, Medical University of 
      Innsbruck, Muellerstrasse 44, 6020 Innsbruck, Austria.
FAU - Weiss, Gunter
AU  - Weiss G
AUID- ORCID: 0000-0003-0709-2158
AD  - Department of Internal Medicine II, Medical University of Innsbruck, Anichstrasse 
      35, 6020 Innsbruck, Austria.
AD  - Christian Doppler Laboratory for Iron Metabolism and Anemia Research, Medical 
      University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria.
LA  - eng
GR  - DOC 82/FWF_/Austrian Science Fund FWF/Austria
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230414
PL  - Switzerland
TA  - Cells
JT  - Cells
JID - 101600052
RN  - 207137-56-2 (Interleukin-4)
RN  - 82115-62-6 (Interferon-gamma)
RN  - 94ZLA3W45F (Arginine)
SB  - IM
MH  - Mice
MH  - Animals
MH  - *Salmonella typhimurium
MH  - *Interleukin-4/metabolism
MH  - Serogroup
MH  - Mice, Inbred C57BL
MH  - Macrophages/metabolism
MH  - Interferon-gamma/metabolism
MH  - Arginine/pharmacology/metabolism
PMC - PMC10137269
OTO - NOTNLM
OT  - Salmonella enterica serovar Typhimurium
OT  - arginase 1
OT  - inducible nitric oxide synthase
OT  - interferon-gamma
OT  - interleukin-4
OT  - intracellular bacteria
OT  - macrophages
OT  - ornithine
OT  - polyamines
COIS- The authors declare no conflict of interest.
EDAT- 2023/05/16 06:42
MHDA- 2023/05/17 06:42
PMCR- 2023/04/14
CRDT- 2023/05/16 01:12
PHST- 2022/12/23 00:00 [received]
PHST- 2023/04/06 00:00 [revised]
PHST- 2023/04/12 00:00 [accepted]
PHST- 2023/05/17 06:42 [medline]
PHST- 2023/05/16 06:42 [pubmed]
PHST- 2023/05/16 01:12 [entrez]
PHST- 2023/04/14 00:00 [pmc-release]
AID - cells12081164 [pii]
AID - cells-12-01164 [pii]
AID - 10.3390/cells12081164 [doi]
PST - epublish
SO  - Cells. 2023 Apr 14;12(8):1164. doi: 10.3390/cells12081164.