Abstract
Trained immunity and immune tolerance have been identified as long-term response patterns of the innate immune system. The causes of these opposing reactions remain elusive. Here, we report about differential inflammatory responses of microglial cells derived from neonatal mouse brain to increasing doses of the endotoxin LPS. Prolonged priming with ultra-low LPS doses provokes trained immunity, i.e., increased production of pro-inflammatory mediators in comparison to the unprimed control. In contrast, priming with high doses of LPS induces immune tolerance, implying decreased production of inflammatory mediators and pronounced release of anti-inflammatory cytokines. Investigation of the signaling processes and cell functions involved in these memory-like immune responses reveals the essential role of phosphoinositide 3-kinase γ (PI3Kγ), one of the phosphoinositide 3-kinase species highly expressed in innate immune cells. Together, our data suggest profound influence of preceding contacts with pathogens on the immune response of microglia. The impact of these interactions—trained immunity or immune tolerance—appears to be shaped by pathogen dose.
Highlights
Innate immune cells act as first front line of the immune response to microbial pathogens
Primed microglial cells showed a distinct biphasic dose-response pattern for the prototypical pro-inflammatory cytokines TNF-α and IL-6, exhibiting enhanced cytokine release after low-dose priming and markedly diminished cytokine measures when microglial cells have been primed with higher LPS dosages (Figures 1B,C,E, Supplementary Figure 7)
The biphasic response patterns of microglia after priming with low and high doses of LPS considerably oppose the effects of LPS dosage on the cytokine production of UP microglial cells (Supplementary Figure 1)
Summary
Innate immune cells act as first front line of the immune response to microbial pathogens. Endotoxins like bacterial lipopolysaccharides (LPS) have been shown to induce host responses to as few as 100 invading Gram-negative bacteria, corresponding to femtomoles of LPS [1,2,3] These highly sensitive reactions set off efficient elimination of the invading microorganisms. Current mechanistic investigations reveal that the long-established tolerance response provoked by repeated LPS challenge is based on similar molecular mechanisms including changes in LPS signaling, epigenetic markers, and chromatin remodeling [7].
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