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Low-dose lipopolysaccharide as an immune regulator for homeostasis maintenance in the central nervous system through transformation to neuroprotective microglia.

ABSTRACT: Microglia, which are tissue-resident macrophages in the brain, play a central role in the brain innate immunity and contribute to the maintenance of brain homeostasis. Lipopolysaccharide is a component of the outer membrane of gram-negative bacteria, and activates immune cells including microglia via Toll-like receptor 4 signaling. Lipopolysaccharide is generally known as an endotoxin, as administration of high-dose lipopolysaccharide induces potent systemic inflammation. Also, it has long been recognized that lipopolysaccharide exacerbates neuroinflammation. In contrast, our study revealed that oral administration of lipopolysaccharide ameliorates Alzheimer's disease pathology and suggested that neuroprotective microglia are involved in this phenomenon. Additionally, other recent studies have accumulated evidence demonstrating that controlled immune training with low-dose lipopolysaccharide prevents neuronal damage by transforming the microglia into a neuroprotective phenotype. Therefore, lipopolysaccharide may not a mere inflammatory inducer, but an immunomodulator that can lead to neuroprotective effects in the brain. In this review, we summarized current studies regarding neuroprotective microglia transformed by immune training with lipopolysaccharide. We state that microglia transformed by lipopolysaccharide preconditioning cannot simply be characterized by their general suppression of proinflammatory mediators and general promotion of anti-inflammatory mediators, but instead must be described by their complex profile comprising various molecules related to inflammatory regulation, phagocytosis, neuroprotection, anti-apoptosis, and antioxidation. In addition, microglial transformation seems to depend on the dose of lipopolysaccharide used during immune training. Immune training of neuroprotective microglia using low-dose lipopolysaccharide, especially through oral lipopolysaccharide administration, may represent an innovative prevention or treatment for neurological diseases; however more vigorous studies are still required to properly modulate these treatments.

SUBMITTER: Mizobuchi H

PROVIDER: S-EPMC8343302 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundLipocalin 2 (Lcn2) is a bacteriostatic factor that may also modulate cellular function, however, little is known concerning the expression or role of Lcn2 in CNS inflammation. Therefore, here we investigated the regulation and possible function of Lcn2 in the CNS following peripheral lipopolysaccharide (LPS) injection in mice.MethodsA murine model for systemic endotoxemia was used in this study. Wild type or Lcn2 KO mice (both genotypes C57BL/6 strain) were given either a single or dual, staggered intraperitoneal injections of purified E. coli LPS or vehicle alone. The brain was examined for the expression and location of Lcn2 mRNA and protein and various markers for neuroinflammation were analyzed.ResultsAlthough undetectable under physiological conditions, both Lcn2 mRNA and protein were induced to high levels in the brain after LPS injection. By contrast, RNA corresponding to the putative Lcn2 (termed 24p3R) receptor was present at high levels in the normal brain and remained unaltered by LPS injection. Differences between Lcn2 and 24p3R mRNA expression were found at the anatomic and cellular level. Endothelial cells, microglia and the choroid plexus but not neurons were identified as the main cellular sources for Lcn2 mRNA in the CNS. By contrast, 24p3R mRNA was detected in neurons and the choroid plexus only. Lcn2 protein was found to have a similar cellular localization as the corresponding RNA transcripts with the exception that subsets of neurons were also strongly positive. Various inflammatory, glial, and iron handling markers were analyzed and found to have similar alterations between WT and Lcn2 KO animals.Conclusions1) Lcn2 production is strongly induced in the CNS by systemic LPS injection, 2) in addition to Lcn2 production at key gateways of bacterial entry to the CNS, neurons may be a target for the actions of Lcn2, which is apparently taken up by these cells, and 3) the cellular functions of Lcn2 in the CNS remain enigmatic.

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Low-dose lipopolysaccharide as an immune regulator for homeostasis maintenance in the central nervous system through transformation to neuroprotective microglia.

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