Chemokine Interleukin-8 (IL-8) in Alzheimer’s and Other Neurodegenerative Diseases

McLarnon, James G.

doi:10.4172/2161-0460.1000273

Cited by 20 publications

(13 citation statements)

References 25 publications

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“…In the tri-culture model, the microglia are the first to develop a ferroptotic signature. Microglia may act as an initiator of ferroptosis and/or inflammation via IL-8 production that leads to neurotoxicity [31]. Additional temporal studies would be required to confirm the microglia-mediated neuronal death in response to iron rather than cell autonomous neuronal ferroptosis.…”

Section: Discussionmentioning

confidence: 99%

Microglia ferroptosis is prevalent in neurodegenerative disease and regulated by SEC24B

Ryan

Zelic

Han

et al. 2021

Preprint

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Iron dysregulation has been implicated in multiple neurodegenerative diseases, including Parkinson’s Disease (PD), Amyotrophic Lateral Sclerosis (ALS), and Multiple Sclerosis (MS). One prominent feature of affected brain regions are iron-loaded microglia, but how iron overload influences microglia physiology and disease response is poorly understood. Here we show that microglia are highly susceptible to ferroptosis, an iron-dependent form of cell death. In a tri-culture of human iPSC-derived neurons, astrocytes, and microglia, under ferroptosis-inducing conditions, microglia undergo a drastic shift in cell state, with increased ferritin levels, disrupted glutathione homeostasis, and altered cytokine signaling. Similar ferroptosis-associated signature (FAS) microglia were uncovered in PD, and the signature was also found in a large cohort of PD patient blood samples, raising the possibility that ferroptosis can be identified clinically. We performed a genome-wide CRISPR screen which revealed a novel regulator of ferroptosis, the vesicle trafficking gene SEC24B. A small molecule screen also nominated several candidates which blocked ferroptosis, some of which are already in clinical use. These data suggest that ferroptosis sits at the interface of cell death and inflammation, and inhibition of this process in microglia and other brain cells may provide new ways for treating neurodegenerative disease.

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Section: Discussionmentioning

confidence: 99%

Microglia ferroptosis is prevalent in neurodegenerative disease and regulated by SEC24B

Ryan

Zelic

Han

et al. 2021

Preprint

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“…Finally, McQualter and co-workers have detected the formation and expansion of inflammatory lesions within the CNS during experimental autoimmune encephalomyelitis, a mouse model for human multiple sclerosis (MS) that is highly dependent on GM-CSF [ 39 ]. All these studies and many others have established or suggested detrimental roles in various brain disorders and their progression (MS, Alzheimer disease (AD), cerebral stroke, ALS, and more) and BBB permeability for these four cytokines that are all upregulated by bryostatin-1 in astrocytes [ 32 , 33 , 40 , 41 ].…”

Section: Discussionmentioning

confidence: 99%

Contrasting effect of the latency-reversing agents bryostatin-1 and JQ1 on astrocyte-mediated neuroinflammation and brain neutrophil invasion

Proust

Barat

Lebœuf

et al. 2017

J Neuroinflammation

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BackgroundDespite effectiveness of the combined antiretroviral therapy, HIV-1 persists in long-lived latently infected cells. Consequently, new therapeutic approaches aimed at eliminating this latent reservoir are currently being developed. A “shock and kill” strategy using latency-reversing agents (LRA) to reactivate HIV-1 has been proposed. However, the impact of LRA on the central nervous system (CNS) remains elusive.MethodsWe used human fetal astrocytes and investigated the effects of several LRA on their functional and secretory activities. Astrocytes were infected with VSV-G-pseudotyped HIV-1 before treatment with various blood-brain barrier (BBB)-permeable LRA at subcytotoxic doses, which allow HIV-1 reactivation based on previous in vitro and clinical studies. Cells and supernatants were then used to evaluate effects of infection and LRA on (i) viability and metabolic activity of astrocytes using a colorimetric MTS assay; (ii) chemokines and proinflammatory cytokines secretion and gene expression by astrocytes using ELISA and RT-qPCR, respectively; (iii) expression of complement component 3 (C3), a proxy for astrogliosis, by RT-qPCR; (iv) glutamate uptake capacity by a fluorometric assay; and (v) modulation of neutrophil transmigration across an in vitro BBB model.ResultsWe demonstrate that bryostatin-1 induces secretion of chemokines CCL2 and IL-8 and proinflammatory cytokines IL-6 and GM-CSF, whereas their production is repressed by JQ1. Bryostatin-1 also increases expression of complement component 3 and perturbs astrocyte glutamate homeostasis. Lastly, bryostatin-1 enhances transmigration of neutrophils across an in vitro blood-brain barrier model and induces formation of neutrophil extracellular traps.ConclusionsThese observations highlight the need to carefully assess the potential harmful effect to the CNS when selecting LRA for HIV-1 reactivation strategies.Electronic supplementary materialThe online version of this article (10.1186/s12974-017-1019-y) contains supplementary material, which is available to authorized users.

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“…In addition, increased plasma levels of IL-6 downregulate the expression of AKT-1 and DROSHA genes thereby possibly affecting the microRNA machinery and many cellular functions [108]. Also, IRS-related chemokines including CXCL-8 contribute to neuroprogressive processes by facilitating migration of leukocytes through the blood brain barrier and sustaining neuroinflammation in the brain thus leading to neurotoxicity [157,158]. Activated Th-1 and M1 subsets stimulate IDO and kynurenine 3-monooxygenase [159] to produce more cytotoxic, excitotoxic, and neurotoxic TRYCATs including picolinic acid, xanthurenic acid and quinolinic acid [71], thereby causing cognitive impairments including in episodic and semantic memory [136].…”

Section: Contributions Of Irs As Well As Cirs To Pathophysiologymentioning

confidence: 99%

The Role of Aberrations in the Immune-inflammatory Reflex System (IRS) and the Compensatory Immune-regulatory Reflex System (CIRS) in Different Phenotypes of Schizophrenia: The IRS-CIRS Theory of Schizophrenia

Roomruangwong¹,

Noto²,

Kanchanatawan³

et al. 2018

Preprint

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In this paper we propose a novel theoretical framework, which was previously developed for major depression and bipolar disorder, namely the compensatory immune-regulatory reflex system (CIRS), as applied to the neuro-immune pathophysiology of schizophrenia and its phenotypes, including first episode psychosis (FEP), acute relapses, chronic and treatment resistant schizophrenia (TRS), comorbid depression, and deficit schizophrenia. These schizophrenia phenotypes and manifestations are accompanied by increased production of positive acute phase proteins, including haptoglobin and α2-macroglobulin, complement factors, and macrophagic M1 (IL-1β, IL-6 and TNF-α), T helper (Th)-1 (interferon-γ and IL-2R), Th-2 (IL-4, IL-5), Th-17 (IL-17) and T regulatory (Treg; IL-10 and transforming growth factor (TGF)-β1) cytokines, cytokine-induced activation of the tryptophan catabolite (TRYCAT) pathway as well as chemokines, including CCL-11 (eotaxin), CCL-2, CCL-3 and CXCL-8. While the immune profiles in the different schizophrenia phenotypes indicate activation of the immune-inflammatory response system (IRS), there are simultaneous signs of CIRS activation, including increased levels of the IL-1 receptor antagonist (sIL-1RA), sIL-2R and tumor necrosis factor-a receptors, Th-2 and Treg phenotypes with increased IL-4 and IL-10 production, and increased levels of TRYCATs and haptoglobin, α2-macroglobulin and other acute phase reactants, which have immune-regulatory and anti-inflammatory effects. Signs of activated IRS and CIRS pathways are also detected in TRS, chronic and deficit schizophrenia indicating that these conditions are accompanied by a new homeostatic setpoint between upregulated IRS and CIRS components. In FEP, increased baseline CIRS activity is a protective factor which may predict favorable clinical outcomes. Moreover, impairments in the CIRS are associated with deficit schizophrenia and greater impairments in semantic and episodic memory. It is concluded that CIRS plays a key role in the pathophysiology of schizophrenia by negatively regulating the primary IRS and contributing to recovery from the acute phase of illness. Components of the CIRS may offer promising therapeutic targets for schizophrenia.

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Chemokine Interleukin-8 (IL-8) in Alzheimer’s and Other Neurodegenerative Diseases

Cited by 20 publications

References 25 publications

Microglia ferroptosis is prevalent in neurodegenerative disease and regulated by SEC24B

Microglia ferroptosis is prevalent in neurodegenerative disease and regulated by SEC24B

Contrasting effect of the latency-reversing agents bryostatin-1 and JQ1 on astrocyte-mediated neuroinflammation and brain neutrophil invasion

The Role of Aberrations in the Immune-inflammatory Reflex System (IRS) and the Compensatory Immune-regulatory Reflex System (CIRS) in Different Phenotypes of Schizophrenia: The IRS-CIRS Theory of Schizophrenia

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