Mechanisms of long-term cognitive dysfunction of sepsis: from blood-borne leukocytes to glial cells

Michels, Monique; Steckert, Amanda V.; Quevedo, João; Barichello, Tatiana; Dal‐Pizzol, Felipe

doi:10.1186/s40635-015-0066-x

Cited by 40 publications

(27 citation statements)

References 156 publications

(157 reference statements)

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“…Severe bacterial infections such as meningitis and sepsis trigger CNS inflammatory pathways that are key drivers of neurologic damage and dysfunction ( 1 – 3 ). Corticosteroids are the principal means used in clinical practice to ameliorate brain inflammation during bacterial meningitis ( 1 ).…”

Section: Introductionmentioning

confidence: 99%

Neuroinvasive Listeria monocytogenes Infection Triggers IFN-Activation of Microglia and Upregulates Microglial miR-155

Zhang

Gipson

et al. 2018

Front. Immunol.

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MicroRNA (miR) miR-155 modulates microglial activation and polarization, but its role in activation of microglia during bacterial brain infection is unclear. We studied miR-155 expression in brains of C57BL/6 (B6.WT) mice infected i.p. with the neuro-invasive bacterial pathogen Listeria monocytogenes (L. monocytogenes). Infected mice were treated with ampicillin starting 2 days (d) post-infection (p.i.) and analyzed 3d, 7d, and 14d p.i. Virulent L. monocytogenes strains EGD and 10403s upregulated miR-155 in whole brain 7 d p.i. whereas infection with avirulent, non-neurotropic Δhly or ΔactA L. monocytogenes mutants did not. Similarly, infection with virulent but not mutated bacteria upregulated IFN-γ mRNA in the brain at 7 d p.i. Upregulation of miR-155 in microglia was confirmed by qPCR of flow cytometry-sorted CD45intCD11bpos brain cells. Subsequently, brain leukocyte influxes and gene expression in sorted microglia were compared in L. monocytogenes-infected B6.WT and B6.Cg-Mir155tm1.1Rsky/J (B6.miR-155−/−) mice. Brain influxes of Ly-6Chigh monocytes and upregulation of IFN-related genes in microglia were similar to B6.WT mice at 3 d p.i. In contrast, by d 7 p.i. expressions of microglial IFN-related genes, including markers of M1 polarization, were significantly lower in B6.miR-155−/− mice and by 14 d p.i., influxes of activated T-lymphocytes were markedly reduced. Notably, CD45highCD11bpos brain cells from B6.miR-155−/− mice isolated at 7 d p.i. expressed 2-fold fewer IFN-γ transcripts than did cells from B6.WT mice suggesting reduced IFN-γ stimulation contributed to dampened gene expression in B6.miR-155−/− microglia. Lastly, in vitro stimulation of 7 d p.i. brain cells with heat-killed L. monocytogenes induced greater production of TNF in B6.miR-155−/− microglia than in B6.WT microglia. Thus, miR-155 affects brain inflammation by multiple mechanisms during neuroinvasive L. monocytogenes infection. Peripheral miR-155 promotes brain inflammation through its required role in optimal development of IFN-γ-secreting lymphocytes that enter the brain and activate microglia. Microglial miR-155 promotes M1 polarization, and also inhibits inflammatory responses to stimulation by heat-killed L. monocytogenes, perhaps by targeting Tab2.

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Section: Introductionmentioning

confidence: 99%

Neuroinvasive Listeria monocytogenes Infection Triggers IFN-Activation of Microglia and Upregulates Microglial miR-155

Zhang

Gipson

et al. 2018

Front. Immunol.

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“…Peripherally produced cytokines can enter the central nervous system (CNS), as sepsis is able to induce transient disruption of the blood-brain barrier (BBB) (10,11). This in turn leads to microglia/astrocyte activation and local production of pro-inflammatory mediators and reactive species (12,13). However, details of the molecular cascades linking systemic inflammation to neuroinflammation and brain dysfunction still need to be better understood.…”

mentioning

confidence: 99%

Receptor for advanced glycation end products mediates sepsis-triggered amyloid-β accumulation, Tau phosphorylation, and cognitive impairment

Gasparotto

Girardi

Somensi

et al. 2018

Journal of Biological Chemistry

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Patients recovering from sepsis have higher rates of CNS morbidities associated with long-lasting impairment of cognitive functions, including neurodegenerative diseases. However, the molecular etiology of these sepsis-induced impairments is unclear. Here, we investigated the role of the receptor for advanced glycation end products (RAGE) in neuroinflammation, neurodegeneration-associated changes, and cognitive dysfunction arising after sepsis recovery. Adult Wistar rats underwent cecal ligation and perforation (CLP), and serum and brain (hippocampus and prefrontal cortex) samples were obtained at days 1, 15, and 30 after the CLP. We examined these samples for systemic and brain inflammation; amyloid-β peptide (Aβ) and Ser-202-phosphorylated Tau (p-Tau) levels; and RAGE, RAGE ligands, and RAGE intracellular signaling. Serum markers associated with the acute proinflammatory phase of sepsis (TNFα, IL-1β, and IL-6) rapidly increased and then progressively decreased during the 30-day period post-CLP, concomitant with a progressive increase in RAGE ligands (S100B, ϵ-[carboxymethyl]lysine, HSP70, and HMGB1). In the brain, levels of RAGE and Toll-like receptor 4, glial fibrillary acidic protein and neuronal nitric-oxide synthase, and Aβ and p-Tau also increased during that time. Of note, intracerebral injection of RAGE antibody into the hippocampus at days 15, 17, and 19 post-CLP reduced Aβ and p-Tau accumulation, Akt/mechanistic target of rapamycin signaling, levels of ionized calcium-binding adapter molecule 1 and glial fibrillary acidic protein, and behavioral deficits associated with cognitive decline. These results indicate that brain RAGE is an essential factor in the pathogenesis of neurological disorders following acute systemic inflammation.

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“…Besides microglia, astrocytes, neurons, and peripheral infiltrating leukocytes are also involved in NI . Astrocytes are critical to maintaining CNS homeostasis, especially at the neurovascular units of the BBB .…”

Section: Human Sepsis and Saementioning

confidence: 99%

“…Moreover, astrocytes form synapses with T cells, becoming an important source of proinflammatory cytokines and chemokines, which may facilitate cell trafficking into and within the CNS . Additionally, astrocytes can migrate to the damaged site and initiate reactive astrogliosis …”

Section: Human Sepsis and Saementioning

confidence: 99%

Sepsis: developing new alternatives to reduce neuroinflammation and attenuate brain injury

Meneses

Cárdenas

Espinosa

et al. 2018

Annals of the New York Academy of Sciences

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Sepsis occurs when a systemic infection induces an uncontrolled inflammatory response that results in generalized organ dysfunction. The exacerbated peripheral inflammation can induce, in turn, neuroinflammation which may result in severe impairment of the central nervous system (CNS). Indeed, the ensuing blood–brain barrier disruption associated with sepsis promotes glial activation and starts a storm of proinflammatory cytokines in the CNS that leads to brain dysfunction in sepsis survivors. Endotoxic shock induced in mice by peripheral injection of lipopolysaccharides closely resembles the peripheral and central inflammation observed in sepsis. In this review, we provide an overview of the neuroinflammatory features in sepsis and of recent progress toward the development of new anti‐neuroinflammatory therapies seeking to reduce mortality and morbidity in sepsis survivors.

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Mechanisms of long-term cognitive dysfunction of sepsis: from blood-borne leukocytes to glial cells

Cited by 40 publications

References 156 publications

Neuroinvasive Listeria monocytogenes Infection Triggers IFN-Activation of Microglia and Upregulates Microglial miR-155

Neuroinvasive Listeria monocytogenes Infection Triggers IFN-Activation of Microglia and Upregulates Microglial miR-155

Receptor for advanced glycation end products mediates sepsis-triggered amyloid-β accumulation, Tau phosphorylation, and cognitive impairment

Sepsis: developing new alternatives to reduce neuroinflammation and attenuate brain injury

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