Memory-Like Responses of Brain Microglia Are Controlled by Developmental State and Pathogen Dose

Area of Science:

• Neuroimmunology
• Innate Immune Memory
• Developmental Neuroscience

Background:

• Microglia, the resident immune cells of the central nervous system (CNS), possess adaptive immune memory, influencing brain homeostasis and disease.
• The factors governing the development and regulation of these dual responses (trained immunity and immune tolerance) in microglia remain incompletely understood.
• Previous research demonstrated that microglia from the newborn brain exhibit characteristics of both trained immunity and immune tolerance following repeated pathogen exposure in a dose-dependent manner.

Purpose of the Study:

• To investigate the impact of developmental stage on the adaptive immune responses of brain microglia.
• To compare microglial responses to ultra-low and high doses of lipopolysaccharide (LPS) in vitro across different murine developmental stages (newborn, mature, aged).

Main Methods:

• Primary microglia cultures were derived from newborn, mature, and aged murine brains.
• Cells were primed in vitro with either ultra-low (1 fg/ml) or high (100 ng/ml) doses of LPS.
• Pro-inflammatory and anti-inflammatory mediator levels (e.g., TNF-α, IL-6, IL-1β, IL-10, Arg-1) and iNOS expression were quantified.

Main Results:

• Priming with ultra-low LPS doses induced trained immunity in newborn microglia, significantly increasing pro-inflammatory mediators and neurotrophic factors (p < 0.05).
• High-dose LPS priming induced immune tolerance, characterized by robust downregulation of pro-inflammatory cytokines and iNOS, irrespective of developmental stage.
• High-dose LPS also upregulated anti-inflammatory mediators (IL-10, Arg-1, TGF-β, MSR1, IL-4) in newborn microglia (p < 0.05), indicating pronounced immune plasticity.

Conclusions:

• Neonate microglia exhibit greater immune response plasticity compared to microglia from mature and aged brains.
• Priming with ultra-low LPS doses may lead to enhanced neuroinflammatory susceptibility in the immature brain via induced trained immunity.
• High-dose LPS priming results in an immunosuppressed phenotype, potentially mitigating excessive damage during recurrent systemic inflammation.