Trained innate immunity: a salient factor in the pathogenesis of neuroimmune psychiatric disorders

Salam, Alex P.; Borsini, Alessandra; Zunszain, Patricia A.

doi:10.1038/mp.2017.186

Cited by 31 publications

(27 citation statements)

References 80 publications

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“…Previous neuropathology potentially attunes microglia to respond more strongly to systemic inflammation (142), including inflammation by chronic mild stress in periadolesence following MIA (86). Consequently, infection could prime microglia towards heightened activation, potentially increasing the risk of developing psychotic symptoms (143); alternatively, the opposite could be true, i.e., that the microglia become tolerant and as such cannot respond flexibly to new stimuli. In terms of potential downstream consequences of such foetal microglial activation, there is an emerging literature implicating the role of microglia in shaping brain development, including the potential for synaptic pruning via the full or partial engulfment [phago-or trogocytosis (144)] and putative degradation of synaptic inputs, a process mediated at least in the rodent visual thalamus in a complement and activity-dependent manner (145), which may also involve other molecular mediators such as TREM2 for example or the fractalkine receptor [CX3CR1; (146)] [potential mechanisms are reviewed in (147)].…”

Section: Experimental Paradigms Of Maternal Infectionmentioning

confidence: 99%

Schizophrenia and Influenza at the Centenary of the 1918-1919 Spanish Influenza Pandemic: Mechanisms of Psychosis Risk

et al. 2020

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Associations between influenza infection and psychosis have been reported since the eighteenth century, with acute "psychoses of influenza" documented during multiple pandemics. In the late 20 th century, reports of a season-of-birth effect in schizophrenia were supported by large-scale ecological and sero-epidemiological studies suggesting that maternal influenza infection increases the risk of psychosis in offspring. We examine the evidence for the association between influenza infection and schizophrenia risk, before reviewing possible mechanisms via which this risk may be conferred. Maternal immune activation models implicate placental dysfunction, disruption of cytokine networks, and subsequent microglial activation as potentially important pathogenic processes. More recent neuroimmunological advances focusing on neuronal autoimmunity following infection provide the basis for a model of infection-induced psychosis, potentially implicating autoimmunity to schizophrenia-relevant protein targets including the Nmethyl-D-aspartate receptor. Finally, we outline areas for future research and relevant experimental approaches and consider whether the current evidence provides a basis for the rational development of strategies to prevent schizophrenia.

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Section: Experimental Paradigms Of Maternal Infectionmentioning

confidence: 99%

Schizophrenia and Influenza at the Centenary of the 1918-1919 Spanish Influenza Pandemic: Mechanisms of Psychosis Risk

et al. 2020

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“…It is well accepted that inflammation in the peripheral organs can influence homeostasis and immune responses in the central nervous system (CNS) [1]. In common neuropsychiatric conditions such as schizophrenia and depression, evidence indicates that neuroinflammation plays a role in the disease pathogenesis [2]. Long-lasting effects of neuroinflammation in such neuropsychiatric conditions are implicated with altered innate immune responses in the absence of specific pathogens [2].…”

Section: Introductionmentioning

confidence: 99%

Innate Immunity and Neuroinflammation in Neuropsychiatric Conditions Including Autism Spectrum Disorders: Role of Innate Immune Memory

Jyonouchi¹

2020

Cytokines

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The neuroimmune network represents a dense network of multiple signals mediated by neurotransmitters, hormones, growth factors, and cytokines produced by multiple lineage cells and is crucial for maintaining neuroimmune homeostasis. Endogenous and exogenous stimuli, which are dangerous to the body, are detected by sensor cells, and they rapidly inform the brain through this network. Innate immunity is thought to play a major role in the neuroimmune network, through cytokines and other mediators released from secretary innate immune cells. Recent research has revealed that innate immunity has its own memory. This is accomplished by metabolic and epigenetic changes. Such changes may result in augmenting immune protection with a risk of excessive inflammatory responses to subsequent stimuli (trained immunity). Alternatively, innate immune memory can induce suppressive effects (tolerance), which may impose a risk of impaired immune defense. Innate immune memory affects the neuroimmune network for a prolonged period, and dysregulated innate immune memory has been implicated with pathogenesis of neuropsychiatric conditions. This chapter summarizes a role of innate immune memory (trained immunity vs. tolerance) in neuroinflammation in association with neuropsychiatric conditions including autism spectrum disorders (ASD).

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“…Traditionally, trained immunity is induced by vaccinations and inflammatory stimulators such as LPS (Mulder, Ochando et al, 2019). However, endogenous alarm signals associated with tissue damage and sterile inflammation can also induce trained immunity through the epigenetic regulation of histone modifications, such as damage-associated molecular patterns (DAMPs), oxLDL, and HDL(Crișan, Netea et al, 2016, Salam, Borsini et al, 2018. It has been reported that DAMPs activate TLR2 to epigenetically modify histone methylation and promote subsequent inflammatory responses.…”

Section: Discussionmentioning

confidence: 99%

“…It has been reported that DAMPs activate TLR2 to epigenetically modify histone methylation and promote subsequent inflammatory responses. DAMPs and TLR2 are critical inflammatory signals involved in stroke-related inflammation, it is reasonable to speculate that trained immunity in the contralateral cortex of microinfarcts was induced similarly (Salam et al, 2018). Alternatively, released DAMPs from CMIs might reach the contralateral cortex through cerebrospinal fluid.…”

Section: Discussionmentioning

confidence: 99%

Cortical microinfarcts potentiate recurrent ischemic injury through NLRP3-dependent trained immunity

Feng

et al. 2020

Preprint

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Microinfarcts are common among the elderly, and patients with microinfarcts are more vulnerable to another stroke. However, the potential effect of microinfarct on recurrent stroke remains elusive. In this study, we investigated the detrimental effect of microinfarct on recurrent stroke in mice. Microinfarct was induced using two-photon laser and photothrombotic stroke was induced in the cortex contralateral to microinfarct four weeks later. We found that CMI could trigger the formation of innate immune memory, which exacerbated the pro-inflammatory response and ischemic injury in second photothrombotic stroke. Furthermore, we clarified the role of NLRP3 inflammasome in the nuclei of microglia, which interacts with the MLL1 complex and thereby increases H3K4 methylation, suggesting that NLRP3 is critical in microinfarct-induced innate immune memory. Additionally, NLRP3 knockout in microglia attenuated microinfarct-induced detrimental effects on recurrent stroke. Our study highlights the detrimental effect of trained immunity on the recurrent stroke and reveals the important role of NLRP3 in mediating the formation of this memory, which may be a therapeutic target to mitigate recurrent strokes.

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Trained innate immunity: a salient factor in the pathogenesis of neuroimmune psychiatric disorders

Cited by 31 publications

References 80 publications

Schizophrenia and Influenza at the Centenary of the 1918-1919 Spanish Influenza Pandemic: Mechanisms of Psychosis Risk

Schizophrenia and Influenza at the Centenary of the 1918-1919 Spanish Influenza Pandemic: Mechanisms of Psychosis Risk

Innate Immunity and Neuroinflammation in Neuropsychiatric Conditions Including Autism Spectrum Disorders: Role of Innate Immune Memory

Cortical microinfarcts potentiate recurrent ischemic injury through NLRP3-dependent trained immunity

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