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Enhanced Macrophage M1 Polarization and Resistance to Apoptosis Enable Resistance to Plague
Emilia Pachulec1, Rym Ben Abdelwahed Bagga1, Lucie Chevallier2
1Yersinia Research Unit, Microbiology Department, Institut Pasteur.
Background:
Susceptibility to infection is in part genetically driven, and C57BL/6 mice resist various pathogens through the proinflammatory response of their M1 macrophages (MPs). However, they are susceptible to plague. It has been reported elsewhere that Mus spretus SEG mice resist plague and develop an immune response characterized by a strong recruitment of MPs.
Methods:
The responses of C57BL/6 and SEG MPs exposed to Yersinia pestis in vitro were examined.
Results:
SEG MPs exhibit a stronger bactericidal activity with higher nitric oxide production, a more proinflammatory polarized cytokine response, and a higher resistance to Y. pestis-induced apoptosis. This response was not specific to Y. pestis and involved a reduced sensitivity to M2 polarization/signal transducer and activator of transcription 6 activation and inhibition of caspase 8. The enhanced M1 profile was inducible in C57BL/6 MPs in vitro, and when transferred to susceptible C57BL/6 mice, these MPs significantly increased survival of bubonic plague.
Conclusions:
MPs can develop an enhanced functional profile beyond the prototypic M1, characterized by an even more potent proinflammatory response coordinated with resistance to killing. This programming plays a key role in the plague-resistance phenotype and may be similarly significant in other highly lethal infections, suggesting that orienting the MP response may represent a new therapeutic approach.
Insights
Mus spretus SEG mice resist plague due to enhanced M1 macrophages (MPs). Programming C57BL/6 MPs to an enhanced M1 profile improved plague survival, suggesting a new therapeutic strategy.
Area of Science:
- Immunology
- Infectious Diseases
- Genetics
Background:
- Genetic factors influence infection susceptibility, with C57BL/6 mice typically resisting pathogens via M1 macrophage (MP) proinflammatory responses.
- Despite general resistance, C57BL/6 mice are susceptible to plague, unlike Mus spretus SEG mice, which exhibit strong MP recruitment during plague infection.
Purpose of the Study:
- To investigate the in vitro responses of C57BL/6 and SEG macrophages (MPs) when exposed to Yersinia pestis.
- To determine if an enhanced M1 macrophage profile can confer plague resistance.
Main Methods:
- Comparative analysis of C57BL/6 and SEG MP responses to Yersinia pestis in vitro.
- Assessment of bactericidal activity, nitric oxide production, cytokine profiles, and apoptosis resistance.
- Induction of enhanced M1 phenotype in C57BL/6 MPs and subsequent transfer to C57BL/6 mice for plague survival studies.
Main Results:
- SEG MPs demonstrated superior bactericidal activity, higher nitric oxide production, a more proinflammatory cytokine response, and enhanced resistance to Y. pestis-induced apoptosis compared to C57BL/6 MPs.
- The enhanced M1 profile in SEG MPs was associated with reduced sensitivity to M2 polarization and inhibition of caspase 8.
- In vitro induction of an enhanced M1 profile in C57BL/6 MPs, when transferred to mice, significantly improved survival rates against bubonic plague.
Conclusions:
- Macrophages can be programmed to an enhanced functional profile beyond the prototypic M1, exhibiting potent proinflammatory responses and resistance to killing.
- This macrophage programming is crucial for the plague-resistance phenotype observed in SEG mice.
- Targeting macrophage responses represents a potential novel therapeutic strategy for highly lethal infections like plague.