Maternal inflammation and diabetes increase the risk for psychiatric disorders in offspring. We hypothesized that these co-occurring risk factors may potentiate each other. To test this, we maternally exposed developing mice in utero to gestational diabetes mellitus (GDM) and/or maternal immune activation (MIA). Fetal mouse brains were exposed to either vehicle, GDM, MIA or GDM+MIA. At gestational day (GD) 12.5, GDM produced a hyperglycemic, hyperleptinemic maternal state, whereas MIA produced significant increases in proinflammatory cytokines and chemokines. Each condition alone resulted in an altered, inflammatory and neurodevelopmental transcriptome profile. In addition, GDM+MIA heightened the maternal inflammatory state and gave rise to a new, specific transcriptional response. This exacerbated response was associated with pathways implicated in psychiatric disorders, including dopamine neuron differentiation and innate immune response. Based on these data, we hypothesize that children born to GDM mothers and exposed to midgestation infections have an increased vulnerability to psychiatric disorder later in life, and this should be tested in follow-up epidemiological studies.

Passive immunization against misfolded toxic proteins is a promising approach to treat neurodegenerative disorders. For effective immunotherapy against Alzheimer's disease, recent clinical data indicate that monoclonal antibodies directed against the amyloid-β peptide should be administered before the onset of symptoms associated with irreversible brain damage. It is therefore critical to develop technologies for continuous antibody delivery applicable to disease prevention. Here, we addressed this question using a bioactive cellular implant to deliver recombinant anti-amyloid-β antibodies in the subcutaneous tissue. An encapsulating device permeable to macromolecules supports the long-term survival of myogenic cells over more than 10 months in immunocompetent allogeneic recipients. The encapsulated cells are genetically engineered to secrete high levels of anti-amyloid-β antibodies. Peripheral implantation leads to continuous antibody delivery to reach plasma levels that exceed 50 µg/ml. In a proof-of-concept study, we show that the recombinant antibodies produced by this system penetrate the brain and bind amyloid plaques in two mouse models of the Alzheimer's pathology. When encapsulated cells are implanted before the onset of amyloid plaque deposition in TauPS2APP mice, chronic exposure to anti-amyloid-β antibodies dramatically reduces amyloid-β40 and amyloid-β42 levels in the brain, decreases amyloid plaque burden, and most notably, prevents phospho-tau pathology in the hippocampus. These results support the use of encapsulated cell implants for passive immunotherapy against the misfolded proteins, which accumulate in Alzheimer's disease and other neurodegenerative disorders.

Increased understanding of the functions of lactate has suggested a close relationship between lactate homeostasis and normal brain activity because of its importance as an energy source and signaling molecule. Here we show that lactate levels affect adult hippocampal neurogenesis. Cerebrovascular-specific deletion of PTEN causes learning and memory deficits and disrupts adult neurogenesis with accompanying lactate accumulation. Consistently, administering lactate to wild-type animals impairs adult hippocampal neurogenesis. The endothelial PTEN/Akt pathway increases monocarboxylic acid transporter 1 (MCT1) expression to enhance lactate transport across the brain endothelium. Moreover, cerebrovascular overexpression of MCT1 or deletion of Akt1 restores MCT1 expression, decreases lactate levels, and normalizes hippocampal neurogenesis and cognitive function in PTEN mutant mice. Together, these findings delineate how the brain endothelium maintains lactate homeostasis and contributes to adult hippocampal neurogenesis and cognitive functions.

Lymphocyte recruitment and activation have been implicated in the progression of cerebral ischemia-reperfusion (I/R) injury, but the roles of specific lymphocyte subpopulations and cytokines during stroke remain to be clarified. Here we demonstrate that the infiltration of T cells into the brain, as well as the cytokines interleukin-23 (IL-23) and IL-17, have pivotal roles in the evolution of brain infarction and accompanying neurological deficits. Blockade of T cell infiltration into the brain by the immunosuppressant FTY720 reduced I/R-induced brain damage. The expression of IL-23, which was derived mostly from infiltrated macrophages, increased on day 1 after I/R, whereas IL-17 levels were elevated after day 3, and this induction of IL-17 was dependent on IL-23. These data, together with analysis of mice genetically disrupted for IL-17 and IL-23, suggest that IL-23 functions in the immediate stage of I/R brain injury, whereas IL-17 has an important role in the delayed phase of I/R injury during which apoptotic neuronal death occurs in the penumbra. Intracellular cytokine staining revealed that gammadeltaT lymphocytes, but not CD4(+) helper T cells, were a major source of IL-17. Moreover, depletion of gammadeltaT lymphocytes ameliorated the I/R injury. We propose that T lymphocytes, including gammadeltaT lymphocytes, could be a therapeutic target for mitigating the inflammatory events that amplify the initial damage in cerebral ischemia.

AIMS:Supranormal levels of aldosterone are associated with an increased cardiovascular risk in humans, and with accelerated atherosclerosis in animal models. Atherosclerosis is a low-grade inflammatory disorder, with monocyte-derived macrophages as major drivers of plaque formation. Monocytes can adopt a long-term pro-inflammatory phenotype after brief stimulation with microbial pathogens or endogenous atherogenic lipoproteins via a process termed trained immunity. In this study, we aimed to investigate whether aldosterone can induce trained immunity in primary human monocytes in vitro and explored the underlying mechanism. METHODS AND RESULTS:We exposed human monocytes to aldosterone for 24 h, after which they were rested to differentiate into monocyte-derived macrophages for 5 days, and re-stimulated with toll-like receptor 2 and 4 ligands on day 6. We demonstrated that aldosterone augments pro-inflammatory cytokine production and reactive oxygen species production in monocyte-derived macrophages after re-stimulation, via the mineralocorticoid receptor. Fatty acid synthesis was identified as a crucial pathway necessary for this induction of trained immunity and pharmacological inhibition of this pathway blunted aldosterone-induced trained immunity. At the level of gene regulation, aldosterone promoted enrichment of the transcriptionally permissive H3K4me3 modification at promoters of genes central to the fatty acid synthesis pathway. CONCLUSION:Aldosterone induces trained immunity in vitro, which is dependent on epigenetically mediated up-regulation of fatty acid synthesis. These data provide mechanistic insight into the contribution of aldosterone to inflammation, atherosclerosis, and cardiovascular disease.

Atherosclerosis, a chronic inflammatory disease of the arterial wall, is among the leading causes of morbidity and mortality worldwide. The persistence of low-grade vascular inflammation has been considered to fuel the development of atherosclerosis. However, fundamental mechanistic understanding of the establishment of non-resolving low-grade inflammation is lacking, and a large number of atherosclerosis-related cardiovascular complications cannot be prevented by current therapeutic regimens. Trained immunity is an emerging new concept describing a prolonged hyperactivation of the innate immune system after exposure to certain stimuli, leading to an augmented immune response to a secondary stimulus. While it exerts beneficial effects for host defense against invading pathogens, uncontrolled persistent innate immune activation causes chronic inflammatory diseases. In light of the above, the long-term over-activation of the innate immune system conferred by trained immunity has been recently hypothesized to serve as a link between non-resolving vascular inflammation and atherosclerosis. Here, we provide an overview of current knowledge on trained immunity triggered by various exogenous and endogenous inducers, with particular emphasis on its pro-atherogenic effects and the underlying intracellular mechanisms that act at both the cellular level and systems level. We also discuss how trained immunity could be mechanistically linked to atherosclerosis from both preclinical and clinical perspectives. This review details the mechanisms underlying the induction of trained immunity by different stimuli, and highlights that the intracellular training programs can be different, though partly overlapping, depending on the stimulus and the biological system. Thus, clinical investigation of risk factor specific innate immune memory is necessary for future use of trained immunity-based therapy in atherosclerosis.

Considerable clinical and epidemiological evidence links Alzheimer's disease (AD) and depression. However, the molecular mechanisms underlying this connection are largely unknown. We reported recently that soluble Aβ oligomers (AβOs), toxins that accumulate in AD brains and are thought to instigate synapse damage and memory loss, induce depressive-like behavior in mice. Here, we report that the mechanism underlying this action involves AβO-induced microglial activation, aberrant TNF-α signaling, and decreased brain serotonin levels. Inactivation or ablation of microglia blocked the increase in brain TNF-α and abolished depressive-like behavior induced by AβOs. Significantly, we identified serotonin as a negative regulator of microglial activation. Finally, AβOs failed to induce depressive-like behavior in Toll-like receptor 4-deficient mice and in mice harboring a nonfunctional TLR4 variant in myeloid cells. Results establish that AβOs trigger depressive-like behavior via a double impact on brain serotonin levels and microglial activation, unveiling a cross talk between brain innate immunity and serotonergic signaling as a key player in mood alterations in AD. SIGNIFICANCE STATEMENT:Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the main cause of dementia in the world. Brain accumulation of amyloid-β oligomers (AβOs) is a major feature in the pathogenesis of AD. Although clinical and epidemiological data suggest a strong connection between AD and depression, the underlying mechanisms linking these two disorders remain largely unknown. Here, we report that aberrant activation of the brain innate immunity and decreased serotonergic tonus in the brain are key players in AβO-induced depressive-like behavior in mice. Our findings may open up new possibilities for the development of effective therapeutics for AD and depression aimed at modulating microglial function.

The mesenchymal microenvironment is increasingly recognized as a major player in immunity. Here we focus on mesenchymal cells located within or in proximity to the blood vessels wall, which include pericytes, adventitial fibroblasts and mesenchymal stromal cells. We discuss recent evidence that these cells play a role in tissue homeostasis, immunity and inflammatory pathologies by multiple mechanisms, including vascular modulation, leucocyte migration, activation or survival in the perivascular space and differentiation into specialized 'effector' mesenchymal cells essential for tissue repair and immunity, such as myofibroblasts and lymphoid stromal cells. When dysregulated, these responses contribute to inflammatory and fibrotic diseases.

The innate immune system plays diverse roles in health and disease. It represents the first line of defense against infection and is involved in tissue repair, wound healing, and clearance of apoptotic cells and cellular debris. Excessive or nonresolving innate immune activation can lead to systemic or local inflammatory complications and cause or contribute to the development of inflammatory diseases. In the brain, microglia represent the key innate immune cells, which are involved in brain development, brain maturation, and homeostasis. Impaired microglial function, either through aberrant activation or decreased functionality, can occur during aging and during neurodegeneration, and the resulting inflammation is thought to contribute to neurodegenerative diseases. This review highlights recent advances in our understanding of the influence of innate immunity on neurodegenerative disorders such as Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, and Huntington's disease.

Astrocytes are believed to bridge interactions between infiltrating lymphocytes and neurons during brain ischemia, but the mechanisms for this action are poorly understood. Here we found that interleukin-15 (IL-15) is dramatically up-regulated in astrocytes of postmortem brain tissues from patients with ischemic stroke and in a mouse model of transient focal brain ischemia. We generated a glial fibrillary acidic protein (GFAP) promoter-controlled IL-15-expressing transgenic mouse (GFAP-IL-15) line and found enlarged brain infarcts, exacerbated neurodeficits after the induction of brain ischemia. In addition, knockdown of IL-15 in astrocytes attenuated ischemic brain injury. Interestingly, the accumulation of CD8 T and natural killer (NK) cells was augmented in these GFAP-IL-15 mice after brain ischemia. Of note, depletion of CD8 T or NK cells attenuated ischemic brain injury in GFAP-IL-15 mice. Furthermore, knockdown of the IL-15 receptor α or blockade of cell-to-cell contact diminished the activation and effector function of CD8 T and NK cells in GFAP-IL-15 mice, suggesting that astrocytic IL-15 is delivered in trans to target cells. Collectively, these findings indicate that astrocytic IL-15 could aggravate postischemic brain damage via propagation of CD8 T and NK cell-mediated immunity.

Microglia are universal sensors of alterations in CNS physiology. These cells integrate complex molecular signals and undergo comprehensive phenotypical remodeling to adapt inflammatory responses. In the last years, single-cell analyses have revealed that microglia exhibit diverse phenotypes during development, growth and disease. Emerging evidence suggests that such phenotype transitions are mediated by reprogramming of cell metabolism. Indeed, metabolic pathways are distinctively altered in activated microglia and are central nodes controlling microglial responses. Microglial lipid metabolism has been specifically involved in the control of microglial activation and effector functions, such as migration, phagocytosis and inflammatory signaling, and minor disturbances in microglial lipid handling associates with altered brain function in disorders featuring neuroinflammation. In this review, we explore new and relevant aspects of microglial metabolism in health and disease. We give special focus on how different branches of lipid metabolism, such as lipid sensing, synthesis and oxidation, integrate and control essential aspects of microglial biology, and how disturbances in these processes associate with aging and the pathogenesis of, for instance, multiple sclerosis and Alzheimer's disease. Finally, challenges and advances in microglial lipid research are discussed.

BACKGROUND:Brain innate immunity is vital for maintaining normal brain functions. Immune homeostatic imbalances play pivotal roles in the pathogenesis of neurological diseases including Parkinson's disease (PD). However, the molecular and cellular mechanisms underlying the regulation of brain innate immunity and their significance in PD pathogenesis are still largely unknown. METHODS:Cre-inducible diphtheria toxin receptor (iDTR) and diphtheria toxin-mediated cell ablation was performed to investigate the impact of neuron-glial antigen 2 (NG2) glia on the brain innate immunity. RNA sequencing analysis was carried out to identify differentially expressed genes in mouse brain with ablated NG2 glia and lipopolysaccharide (LPS) challenge. Neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice were used to evaluate neuroinflammatory response in the presence or absence of NG2 glia. The survival of dopaminergic neurons or glial cell activation was evaluated by immunohistochemistry. Co-cultures of NG2 glia and microglia were used to examine the influence of NG2 glia to microglial activation. RESULTS:We show that NG2 glia are required for the maintenance of immune homeostasis in the brain via transforming growth factor-β2 (TGF-β2)-TGF-β type II receptor (TGFBR2)-CX3C chemokine receptor 1 (CX3CR1) signaling, which suppresses the activation of microglia. We demonstrate that mice with ablated NG2 glia display a profound downregulation of the expression of microglia-specific signature genes and remarkable inflammatory response in the brain following exposure to endotoxin lipopolysaccharides. Gain- or loss-of-function studies show that NG2 glia-derived TGF-β2 and its receptor TGFBR2 in microglia are key regulators of the CX3CR1-modulated immune response. Furthermore, deficiency of NG2 glia contributes to neuroinflammation and nigral dopaminergic neuron loss in MPTP-induced mouse PD model. CONCLUSIONS:These findings suggest that NG2 glia play a critical role in modulation of neuroinflammation and provide a compelling rationale for the development of new therapeutics for neurological disorders.

Cerebral malaria (CM) is a life-threatening neurological syndrome caused by infection afflicting mainly children in Africa. Current pathogenesis models implicate parasite and host-derived factors in impairing brain vascular endothelium (BVE) integrity. Sequestration of -infected red blood cells (iRBCs) in brain microvessels is a hallmark of CM pathology. However, the precise mechanisms driving loss of blood-brain barrier (BBB) function with consequent brain injury are still unsettled and it is plausible that distinct pathophysiology trajectories are involved. Studies in humans and in the mouse model of CM indicate that inflammatory reactions intertwined with microcirculatory and coagulation disturbances induce alterations in vascular permeability and impair BBB integrity. Yet, the role of BVE as initiator of immune responses against parasite molecules and iRBCs is largely unexplored. Brain endothelial cells express pattern recognition receptors (PRR) and are privileged sensors of blood-borne infections. Here, we focus on the hypothesis that innate responses initiated by BVE and subsequent interactions with immune cells are critical to trigger local effector immune functions and induce BBB damage. Uncovering mechanisms of BVE involvement in sensing infection, recruiting of immune cells and directing immune effector functions could reveal pharmacological targets to promote BBB protection with potential applications in CM clinical management.