Genetic ablation of soluble tumor necrosis factor with preservation of membrane tumor necrosis factor is associated with neuroprotection after focal cerebral ischemia

Madsen, Pernille M.; Clausen, Bettina Hjelm; Degn, Matilda; Thyssen, Stine; Kristensen, Lotte K.; Svensson, Martina; Ditzel, Nicholas; Finsen, Bente; Deierborg, Tomas; Brambilla, Roberta; Lambertsen, Kate Lykke

doi:10.1177/0271678x15610339

Cited by 45 publications

(62 citation statements)

References 99 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Using the open field, rotarod, and Y-maze tests, we previously demonstrated that mTNF Δ/Δ mice display no obvious behavioral abnormalities [12]. This was further validated in the present study using the EPM test.…”

Section: Resultssupporting

confidence: 75%

“…Homozygous mTNF Δ/Δ and mTNF wt/wt littermates were obtained by crossing heterozygous mTNF Δ/wt mice at the Biomedical Laboratory, University of Southern Denmark (SDU) [12, 21]. These mice were originally generated by replacing the endogenous TNF allele with Δ1–9, K11E TNF allele [21].…”

Section: Methodsmentioning

confidence: 99%

“…We have previously performed a thorough behavioral assessment of mTNF Δ/Δ in naïve conditions and found no differences in behavioral phenotype compared to mTNF wt/wt littermates [12]. …”

Section: Methodsmentioning

confidence: 99%

“…Whole spinal cord protein samples from mTNF Δ/Δ and mTNF wt/wt mice exposed to SCI and allowed 3-day survival in addition to naïve mTNF Δ/Δ and mTNF wt/wt mice were obtained and protein extractions were prepared as previously described [11, 12]. …”

Section: Methodsmentioning

confidence: 99%

“…In experimental focal cerebral ischemia, an acute CNS injury, microglial-derived mTNF has been shown to be neuroprotective through binding to TNFR1 [9–12]. However, in SCI the data are conflicting.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Genetic Ablation of Soluble TNF Does Not Affect Lesion Size and Functional Recovery after Moderate Spinal Cord Injury in Mice

Ellman

Degn

Lund

et al. 2016

Mediators of Inflammation

Self Cite

View full text Add to dashboard Cite

Traumatic spinal cord injury (SCI) is followed by an instant increase in expression of the microglial-derived proinflammatory cytokine tumor necrosis factor (TNF) within the lesioned cord. TNF exists both as membrane-anchored TNF (mTNF) and as cleaved soluble TNF (solTNF). We previously demonstrated that epidural administration of a dominant-negative inhibitor of solTNF, XPro1595, to the contused spinal cord resulted in changes in Iba1 protein expression in microglia/macrophages, decreased lesion volume, and improved locomotor function. Here, we extend our studies using mice expressing mTNF, but no solTNF (mTNFΔ/Δ), to study the effect of genetic ablation of solTNF on SCI. We demonstrate that TNF levels were significantly decreased within the lesioned spinal cord 3 days after SCI in mTNFΔ/Δ mice compared to littermates. This decrease did, however, not translate into significant changes in other pro- and anti-inflammatory cytokines (IL-10, IL-1β, IL-6, IL-5, IL-2, CXCL1, CCL2, or CCL5), despite a tendency towards increased IL-10 and decreased IL-1β, TNFR1, and TNFR2 levels in mTNFΔ/Δ mice. In addition, microglial and leukocyte infiltration, activation state (Iba1, CD11b, CD11c, CD45, and MHCII), lesion size, and functional outcome after moderate SCI were comparable between genotypes. Collectively, our data demonstrate that genetic ablation of solTNF does not significantly modulate postlesion outcome after SCI.

show abstract

Section: Resultssupporting

confidence: 75%

Section: Methodsmentioning

confidence: 99%

“…We have previously performed a thorough behavioral assessment of mTNF Δ/Δ in naïve conditions and found no differences in behavioral phenotype compared to mTNF wt/wt littermates [12]. …”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Genetic Ablation of Soluble TNF Does Not Affect Lesion Size and Functional Recovery after Moderate Spinal Cord Injury in Mice

Ellman

Degn

Lund

et al. 2016

Mediators of Inflammation

Self Cite

View full text Add to dashboard Cite

show abstract

Cytokines as therapeutic targets for cardio- and cerebrovascular diseases

et al. 2021

View full text Add to dashboard Cite

Despite major advances in prevention and treatment, cardiac and cerebral atherothrombotic complications still account for substantial morbidity and mortality worldwide. In this context, inflammation is involved in the chronic process leading atherosclerotic plaque formation and its complications, as well as in the maladaptive response to acute ischemic events. For this reason, modulation of inflammation is nowadays seen as a promising therapeutic strategy to counteract the burden of cardio- and cerebrovascular disease. Being produced and recognized by both inflammatory and vascular cells, the complex network of cytokines holds key functions in the crosstalk of these two systems and orchestrates the progression of atherothrombosis. By binding to membrane receptors, these soluble mediators trigger specific intracellular signaling pathways eventually leading to the activation of transcription factors and a deep modulation of cell function. Both stimulatory and inhibitory cytokines have been described and progressively reported as markers of disease or interesting therapeutic targets in the cardiovascular field. Nevertheless, cytokine inhibition is burdened by harmful side effects that will most likely prevent its chronic use in favor of acute administrations in well-selected subjects at high risk. Here, we summarize the current state of knowledge regarding the modulatory role of cytokines on atherosclerosis, myocardial infarction, and stroke. Then, we discuss evidence from clinical trials specifically targeting cytokines and the potential implication of these advances into daily clinical practice.

show abstract

Cell therapy centered on IL-1Ra is neuroprotective in experimental stroke

et al. 2016

Self Cite

View full text Add to dashboard Cite

Cell-based therapies are emerging as new promising treatments in stroke. However, their functional mechanism and therapeutic potential during early infarct maturation has so far received little attention. Here, we asked if cell-based delivery of the interleukin-1 receptor antagonist (IL-1Ra), a known neuroprotectant in stroke, can promote neuroprotection, by modulating the detrimental inflammatory response in the tissue at risk. We show by the use of IL-1Ra-overexpressing and IL-1Ra-deficient mice that IL-1Ra is neuroprotective in stroke. Characterization of the cellular and spatiotemporal production of IL-1Ra and IL-1α/β identifies microglia, not infiltrating leukocytes, as the major sources of IL-1Ra after experimental stroke, and shows IL-1Ra and IL-1β to be produced by segregated subsets of microglia with a small proportion of these cells co-expressing IL-1α. Reconstitution of whole body irradiated mice with IL-1Ra-producing bone marrow cells is associated with neuroprotection and recruitment of IL-1Ra-producing leukocytes after stroke. Neuroprotection is also achieved by therapeutic injection of IL-1Ra-producing bone marrow cells 30 min after stroke onset, additionally improving the functional outcome in two different stroke models. The IL-1Ra-producing bone marrow cells increase the number of IL-1Ra-producing microglia, reduce the availability of IL-1β, and modulate mitogen-activated protein kinase (MAPK) signaling in the ischemic cortex. The importance of these results is underlined by demonstration of IL-1Ra-producing cells in the human cortex early after ischemic stroke. Taken together, our results attribute distinct neuroprotective or neurotoxic functions to segregated subsets of microglia and suggest that treatment strategies increasing the production of IL-1Ra by infiltrating leukocytes or microglia may also be neuroprotective if applied early after stroke onset in patients.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-016-1541-5) contains supplementary material, which is available to authorized users.

show abstract

Genetic ablation of soluble tumor necrosis factor with preservation of membrane tumor necrosis factor is associated with neuroprotection after focal cerebral ischemia

Cited by 45 publications

References 99 publications

Genetic Ablation of Soluble TNF Does Not Affect Lesion Size and Functional Recovery after Moderate Spinal Cord Injury in Mice

Genetic Ablation of Soluble TNF Does Not Affect Lesion Size and Functional Recovery after Moderate Spinal Cord Injury in Mice

Cytokines as therapeutic targets for cardio- and cerebrovascular diseases

Cell therapy centered on IL-1Ra is neuroprotective in experimental stroke

Contact Info

Product

Resources

About