Conditional ablation of myeloid TNF increases lesion volume after experimental stroke in mice, possibly via altered ERK1/2 signaling

Clausen, Bettina Hjelm; Degn, Matilda; Sivasaravanaparan, Mithula; Fogtmann, Torben; Andersen, Maria Gammelstrup; Trojanowsky, Michelle; Gao, Han; Hvidsten, Svend; Baun, Christina; Deierborg, Tomas; Finsen, Bente; Kristensen, Bjarne Winther; Bak, Sara Thornby; Meyer, Morten; Jae, Lee,; Nedospasov, Sergei A.; Brambilla, Roberta; Lambertsen, Kate Lykke

doi:10.1038/srep29291

Cited by 36 publications

(37 citation statements)

References 64 publications

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“…5E). It is worth noting that neuronal expression of Cre recombinase in LysM Cre mice has been reported by various groups including ours (Clausen et al, 2016; Orthgiess et al, 2016). However, since TNFR2 is virtually absent in CNS neurons (Brambilla et al, 2011; Zhang et al, 2014), neuronal Cre activity should not affect TNFR2 expression in LysM Cre : Tnfrsf1b fl/fl mice.…”

Section: Resultssupporting

confidence: 59%

Opposing Functions of Microglial and Macrophagic TNFR2 in the Pathogenesis of Experimental Autoimmune Encephalomyelitis

et al. 2017

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Summary In multiple sclerosis (MS), soluble tumor necrosis factor (TNF) is detrimental via activation of TNF receptor 1 (TNFR1), whereas transmembrane TNF is beneficial primarily by activating TNF receptor 2 (TNFR2). Here we investigate the role of TNFR2 in microglia and monocytes/macrophages in experimental autoimmune encephalomyelitis (EAE), a model of MS, by cell-specific gene targeting. We show that TNFR2 ablation in microglia leads to early onset of EAE with increased leukocyte infiltration, T cell activation, and demyelination in the central nervous system (CNS). Conversely, TNFR2 ablation in monocytes/macrophages results in EAE suppression with impaired peripheral T cell activation, and reduced CNS T cell infiltration and demyelination. Our work uncovers a dichotomy of function for TNFR2 in myeloid cells, with microglial TNFR2 providing protective signals to contain disease, and monocyte/macrophagic TNFR2 driving immune activation and EAE initiation. This must be taken into account when targeting TNFR2 for therapeutic purposes in neuroinflammatory diseases.

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Section: Resultssupporting

confidence: 59%

Opposing Functions of Microglial and Macrophagic TNFR2 in the Pathogenesis of Experimental Autoimmune Encephalomyelitis

et al. 2017

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“…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%

“…To measure cytokine, chemokine, and TNFR protein levels by the MSD Mouse Proinflammatory V-Plex Plus Kit (IFN γ , IL-1 β , IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p70, CXCL1, and TNF; K15012C, Mesoscale) and mouse TNF-RI, TNF-RII, RANTES, and MCP-1 Ultra-Sensitive Kits (Mesoscale), we used a SECTOR Imager 6000 (Mesoscale Discovery) Plate Reader according to the manufacturer's instructions. Samples were diluted twofold in Diluent 41 prior to measurement and samples were run in duplicate [11]. Data was analyzed using MSD Discovery Workbench software.…”

Section: Methodsmentioning

confidence: 99%

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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

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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.

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“…Although TNF‐α or CX3CR1 knockout mice showed reduced functional deficits compared to wild‐type mice acutely post‐TBI, their functional recovery over time was impaired and cortical damage was increased . Similarly, TNF‐α was involved in both secondary brain damage and regenerative recovery after experimental stroke . The pathologic involvement of inflammation is supported by evidence that excessive brain levels of IL‐1β, IL‐6, TNF‐α (exceeding several times their serum changes), or HMGB1 contribute to experimental acute and chronic seizures and SE‐induced epileptogenesis .…”

Section: Inflammatory Processes After Acquired Brain Injuriesmentioning

confidence: 99%

Commonalities in epileptogenic processes from different acute brain insults: Do they translate?

et al. 2017

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Summary The most common forms of acquired epilepsies arise following acute brain insults such as traumatic brain injury, stroke, or central nervous system infections. Treatment is effective for only 60%‐70% of patients and remains symptomatic despite decades of effort to develop epilepsy prevention therapies. Recent preclinical efforts are focused on likely primary drivers of epileptogenesis, namely inflammation, neuron loss, plasticity, and circuit reorganization. This review suggests a path to identify neuronal and molecular targets for clinical testing of specific hypotheses about epileptogenesis and its prevention or modification. Acquired human epilepsies with different etiologies share some features with animal models. We identify these commonalities and discuss their relevance to the development of successful epilepsy prevention or disease modification strategies. Risk factors for developing epilepsy that appear common to multiple acute injury etiologies include intracranial bleeding, disruption of the blood‐brain barrier, more severe injury, and early seizures within 1 week of injury. In diverse human epilepsies and animal models, seizures appear to propagate within a limbic or thalamocortical/corticocortical network. Common histopathologic features of epilepsy of diverse and mostly focal origin are microglial activation and astrogliosis, heterotopic neurons in the white matter, loss of neurons, and the presence of inflammatory cellular infiltrates. Astrocytes exhibit smaller K+ conductances and lose gap junction coupling in many animal models as well as in sclerotic hippocampi from temporal lobe epilepsy patients. There is increasing evidence that epilepsy can be prevented or aborted in preclinical animal models of acquired epilepsy by interfering with processes that appear common to multiple acute injury etiologies, for example, in post–status epilepticus models of focal epilepsy by transient treatment with a trkB/PLCγ1 inhibitor, isoflurane, or HMGB1 antibodies and by topical administration of adenosine, in the cortical fluid percussion injury model by focal cooling, and in the albumin posttraumatic epilepsy model by losartan. Preclinical studies further highlight the roles of mTOR1 pathways, JAK‐STAT3, IL‐1R/TLR4 signaling, and other inflammatory pathways in the genesis or modulation of epilepsy after brain injury. The wealth of commonalities, diversity of molecular targets identified preclinically, and likely multidimensional nature of epileptogenesis argue for a combinatorial strategy in prevention therapy. Going forward, the identification of impending epilepsy biomarkers to allow better patient selection, together with better alignment with multisite preclinical trials in animal models, should guide the clinical testing of new hypotheses for epileptogenesis and its prevention.

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Conditional ablation of myeloid TNF increases lesion volume after experimental stroke in mice, possibly via altered ERK1/2 signaling

Cited by 36 publications

References 64 publications

Opposing Functions of Microglial and Macrophagic TNFR2 in the Pathogenesis of Experimental Autoimmune Encephalomyelitis

Opposing Functions of Microglial and Macrophagic TNFR2 in the Pathogenesis of Experimental Autoimmune Encephalomyelitis

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

Commonalities in epileptogenic processes from different acute brain insults: Do they translate?

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