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Macrophages from IL-12p40-deficient mice have a bias toward the M2 activation profile
Karina R B Bastos1, José M Alvarez, Cláudio R F Marinho
1Department of Immunology, Instituto de Ciências Biomédicas, Universidade de São Paulo, Brazil.
Abstract:
Recent studies have provided evidence that macrophages from Th1-prone mouse strains respond with an M1 profile, and macrophages from Th2-prone mouse strains respond with an M2 profile, characterized by the dominant production of NO or TGF-beta 1, respectively. We have shown that peritoneal macrophages from IL-12p40 gene knockout mice have a bias toward the M2 profile, spontaneously secreting large amounts of TGF-beta 1 and responding to rIFN-gamma with weak NO production. Moreover, IL-12p40KO macrophages are more permissive to Trypanosoma cruzi replication than their wild-type littermate cells. Prolonged incubation with rIL-12 fails to reverse the M2 polarization of IL-12p40KO macrophages. However, TGF-beta 1 is directly implicated in sustaining the M2 profile because its inhibition increases NO release from IL-12p40KO macrophages. IFN-gamma deficiency is apparently not the reason for TGF-beta 1 up-regulation, because rIFN-gamma KO macrophages produce normal amounts of this cytokine. These findings raise the possibility that IL-12 has a central role in driving macrophage polarization, regulating their intrinsic ability to respond against intracellular parasites.
Insights
Interleukin-12 (IL-12) drives macrophage polarization towards an M1 profile, crucial for fighting intracellular parasites. Its absence leads to M2 bias, hindering parasite response.
Area of Science:
- Immunology
- Cell Biology
- Parasitology
Background:
- Macrophages exhibit M1 or M2 profiles based on T-helper cell responses.
- M1 macrophages produce nitric oxide (NO), while M2 macrophages produce TGF-beta 1.
Purpose of the Study:
- To investigate the role of IL-12p40 in macrophage polarization and response to Trypanosoma cruzi.
Main Methods:
- Utilized IL-12p40 gene knockout (KO) mice.
- Analyzed peritoneal macrophage polarization (M1/M2 profiles).
- Assessed nitric oxide (NO) and TGF-beta 1 production.
- Evaluated Trypanosoma cruzi replication in macrophages.
Main Results:
- IL-12p40 KO macrophages showed M2 bias, with high TGF-beta 1 and low NO production.
- IL-12p40 KO macrophages were more permissive to Trypanosoma cruzi.
- Inhibiting TGF-beta 1 increased NO release in IL-12p40 KO macrophages.
- Recombinant IL-12 failed to reverse M2 polarization in KO macrophages.
Conclusions:
- IL-12p40 is critical for driving M1 macrophage polarization.
- TGF-beta 1 sustains the M2 profile in IL-12p40 deficient macrophages.
- IL-12 plays a central role in regulating macrophage anti-parasitic responses.