Abstract
Microglia, the innate immune cells of the central nervous system, feature adaptive immune memory with implications for brain homeostasis and pathologies. However, factors involved in the emergence and regulation of these opposing responses in microglia have not been fully addressed. Recently, we showed that microglia from the newborn brain display features of trained immunity and immune tolerance after repeated contact with pathogens in a dose-dependent manner. Here, we evaluate the impact of developmental stage on adaptive immune responses of brain microglia after repeated challenge with ultra-low (1 fg/ml) and high (100 ng/ml) doses of the endotoxin LPS in vitro. We find that priming of naïve microglia derived from newborn but not mature and aged murine brain with ultra-low LPS significantly increased levels of pro-inflammatory mediators TNF-α, IL-6, IL-1β, MMP-9, and iNOS as well as neurotrophic factors indicating induction of trained immunity (p < 0.05). In contrast, stimulation with high doses of LPS led to a robust downregulation of pro-inflammatory cytokines and iNOS independent of the developmental state, indicating induced immune tolerance. Furthermore, high-dose priming with LPS upregulated anti-inflammatory mediators IL-10, Arg-1, TGF- β, MSR1, and IL-4 in newborn microglia (p < 0.05). Our data indicate pronounced plasticity of the immune response of neonate microglia compared with microglia derived from mature and aged mouse brain. Induced trained immunity after priming with ultra-low LPS doses may be responsible for enhanced neuro-inflammatory susceptibility of immature brain. In contrast, the immunosuppressed phenotype following high-dose LPS priming might be prone to attenuate excessive damage after recurrent systemic inflammation.
Highlights
Microglia are the resident macrophage population that control the patterning and wiring of the brain in early development and contribute to homeostasis throughout life [1,2,3,4]
Microglial priming with the ultra-low LPS dose (ULP) followed by a standard fixed LPS dose 5 days later further increased levels of TNF-α (Figures 1B,C), IL-6 (Figures 1D,E), and IL-1β (Figure 1F) in newborn microglia, indicating trained immunity (p < 0.05)
Corroborating our previous report [14, 15, 18], priming of neonatal microglia with low doses of LPS was found to increase release of pro-inflammatory cytokines after the second challenge, whereas priming the cells with high doses of LPS induces tolerance. These findings fit into the paradigm of pathogen dose-dependent training and tolerance responses recently developed for peripheral innate immune cells [28, 29]
Summary
Microglia are the resident macrophage population that control the patterning and wiring of the brain in early development and contribute to homeostasis throughout life [1,2,3,4]. There is growing evidence indicating that microglial cells may lose the ability to retransform to a completely naïve status after activation and may remain as “postactivated” or “primed” microglia, exhibiting potential neuropathological relevance [2]. In this connection, it has been demonstrated that peripheral inflammatory challenges in adult mice induce long-term alterations in microglial response, exhibiting either enhanced or suppressed immune functions possibly exacerbating or alleviating brain pathology in mouse models [14, 15]. In agreement with previous studies on monocytes [reviewed in [17]], we recently showed that opposite immune responses of IIM can be induced in microglia as a function of pathogen dose, revealed for the endotoxin LPS [14, 15, 18]
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