Soluble TNF Receptor 1-Secreting <i>ex Vivo</i>-Derived Dendritic Cells Reduce Injury After Stroke

Works, Melissa; Koenig, Jenny; Sapolsky, Robert M.

doi:10.1038/jcbfm.2013.100

Cited by 24 publications

(15 citation statements)

References 30 publications

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“…This effect was ascribed to sTNF-α R1 competing for solTNF with TNFR1 receptors, supporting the hypothesis that ablating solTNF is beneficial in ischemic stroke. This is in line with a preclinical study showing that intra-arterial injection of solTNFR1-overexpressing dendritic cells 6 h after tMCAO reduces infarct size and inflammation 3 days post-stroke [ 186 ] (Table 1 ).…”

Section: Cytokines and Cytokine Therapies In Experimental And Human Ssupporting

confidence: 88%

Post-stroke inflammation—target or tool for therapy?

2018

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Inflammation is currently considered a prime target for the development of new stroke therapies. In the acute phase of ischemic stroke, microglia are activated and then circulating immune cells invade the peri-infarct and infarct core. Resident and infiltrating cells together orchestrate the post-stroke inflammatory response, communicating with each other and the ischemic neurons, through soluble and membrane-bound signaling molecules, including cytokines. Inflammation can be both detrimental and beneficial at particular stages after a stroke. While it can contribute to expansion of the infarct, it is also responsible for infarct resolution, and influences remodeling and repair. Several pre-clinical and clinical proof-of-concept studies have suggested the effectiveness of pharmacological interventions that target inflammation post-stroke. Experimental evidence shows that targeting certain inflammatory cytokines, such as tumor necrosis factor, interleukin (IL)-1, IL-6, and IL-10, holds promise. However, as these cytokines possess non-redundant protective and immunoregulatory functions, their neutralization or augmentation carries a risk of unwanted side effects, and clinical translation is, therefore, challenging. This review summarizes the cell biology of the post-stroke inflammatory response and discusses pharmacological interventions targeting inflammation in the acute phase after a stroke that may be used alone or in combination with recanalization therapies. Development of next-generation immune therapies should ideally aim at selectively neutralizing pathogenic immune signaling, enhancing tissue preservation, promoting neurological recovery and leaving normal function intact.

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Section: Cytokines and Cytokine Therapies In Experimental And Human Ssupporting

confidence: 88%

Post-stroke inflammation—target or tool for therapy?

2018

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“…Current clinical treatment of ischemic stroke concentrates on dissolving and/or removing the clot, without much focus on the secondary damage that occurs as part of the inflammatory ischemic cascade (Works et al . ). Inflammation is known to play a major role in the pathophysiology of stroke and progression of damage post‐stroke (Vila et al .…”

Section: Discussionmentioning

confidence: 97%

Rapid mitochondrial dysfunction mediates TNF‐alpha‐induced neurotoxicity

Doll

Rellick

Barr

et al. 2015

Journal of Neurochemistry

136

120

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Tumor necrosis factor alpha (TNF-α) is known to exacerbate ischemic brain injury; however, the mechanism is unknown. Previous studies have evaluated the effects of TNF-α on neurons with long exposures to high doses of TNF-α, which is not pathophysiologically relevant. We characterized the rapid effects of TNF-α on basal respiration, ATP production, and maximal respiration using pathophysiologically relevant, post-stroke concentrations of TNF-α. We observed a reduction in mitochondrial function as early as 1.5 h after exposure to low doses of TNF-α, followed by a decrease in cell viability in HT-22 cells and primary neurons. Subsequently, we used the HT-22 cell line to determine the mechanism by which TNF-α causes a rapid and profound reduction in mitochondrial function. Pre-treating with TNF-R1 antibody, but not TNF-R2 antibody, ameliorated the neurotoxic effects of TNF-α, indicating that TNF-α exerts its neurotoxic effects through TNF-R1. We observed an increase in caspase 8 activity and a decrease in mitochondrial membrane potential after exposure to TNF-α which resulted in a release of cytochrome c from the mitochondria into the cytosol. These novel findings indicate for the first time that an acute exposure to pathophysiologically relevant concentrations of TNF-α has neurotoxic effects mediated by a rapid impairment of mitochondrial function.

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“…expanded on these findings to derive DCs to over‐express soluble TNF receptor 1, which ultimately blocks TNF‐ α bioavailability. They injected these DCs into rats who had undergone tMCAO 6 hr earlier and saw reduced infarct volume compared with rats who received DCs expressing GFP lentivirus . Using the quick infiltration of DCs and the prolonged time they reside in the CNS may provide a unique and novel approach to drug delivery in human stroke patients.…”

Section: Dendritic Cells Are the Bridge To Adaptive Immunity Followinmentioning

confidence: 99%

Immune responses in stroke: how the immune system contributes to damage and healing after stroke and how this knowledge could be translated to better cures?

et al. 2018

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Stroke is one of the leading causes of death and disability worldwide. The long-standing dogma that stroke is exclusively a vascular disease has been questioned by extensive clinical findings of immune factors that are associated mostly with inflammation after stroke. These have been confirmed in preclinical studies using experimental animal models. It is now accepted that inflammation and immune mediators are critical in acute and long-term neuronal tissue damage and healing following thrombotic and ischaemic stroke. Despite mounting information delineating the role of the immune system in stroke, the mechanisms of how inflammatory cells and their mediators are involved in stroke-induced neuroinflammation are still not fully understood. Currently, there is no available treatment for targeting the acute immune response that develops in the brain during cerebral ischaemia. No new treatment has been introduced to stroke therapy since the discovery of tissue plasminogen activator therapy in 1996. Here, we review current knowledge of the immunity of stroke and identify critical gaps that hinder current therapies. We will discuss advances in the understanding of the complex innate and adaptive immune responses in stroke; mechanisms of immune cell-mediated and factor-mediated vascular and tissue injury; immunity-induced tissue repair; and the importance of modulating immunity in stroke.

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Soluble TNF Receptor 1-Secreting ex Vivo-Derived Dendritic Cells Reduce Injury After Stroke

Cited by 24 publications

References 30 publications

Post-stroke inflammation—target or tool for therapy?

Post-stroke inflammation—target or tool for therapy?

Rapid mitochondrial dysfunction mediates TNF‐alpha‐induced neurotoxicity

Immune responses in stroke: how the immune system contributes to damage and healing after stroke and how this knowledge could be translated to better cures?

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