TNF and its receptors in the CNS: The essential, the desirable and the deleterious effects (original) (raw)
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Research Square (Research Square), 2021
BACKGROUND During in ammatory demyelination TNF receptor 1 (TNFR1) mediates detrimental proin ammatory effects of soluble TNF, whereas TNFR2 mediates bene cial effects of transmembrane TNF through oligodendrocytes, microglia, and possibly other cell types. This model supports use of selective inhibitors of soluble TNF/TNFR1 as antin ammatory drugs for CNS disease. A potential obstacle is the neuroprotective effect of soluble TNF pretreatment described in cultured neurons, but the in vivo relevance is unknown. METHODS To address this question we generated mice with neuron-speci c depletion of TNFR1, TNFR2 or IKKβ and applied experimental models of in ammatory demyelination and acute and preconditioning glutamate excitotoxicity. We also investigated the molecular and cellular requirements of soluble TNF (and therefore TNFR1) neuroprotection by generating astrocyte-neuron co-cultures with different combinations of wildtype and TNF and TNF receptor knockout cells and measuring NMDA excitotoxicity in vitro. RESULTS Neither neuronal TNFR1 nor TNFR2 protected mice during in ammatory demyelination. In fact, both neuronal TNFR1 and neuronal IKKβ promoted microglial responses and tissue injury, and TNFR1 was further required for oligodendrocyte loss and axonal damage in cuprizone demyelination. In contrast, neuronal TNFR2 increased preconditioning protection in a kainic acid excitotoxicity model in mice, and limited hippocampal neuron death. The neuroprotective effects of neuronal TNFR2 observed in vivo were further investigated in vitro. Here as expected, pretreatment of astrocyte-neuron co-cultures with soluble TNF protected them against NMDA excitotoxicity. However, protection was dependent on astrocyte, not neuronal TNFR1, on astrocyte transmembrane TNF-neuronal TNFR2 interactions, and was reproduced by a TNFR2 agonist. CONCLUSIONS These results demonstrate that neuronal TNF receptors perform fundamentally different roles in CNS pathology in vivo, with neuronal TNFR1 and IKKβ promoting microglial in ammation and neurotoxicity in demyelination, and neuronal TNFR2 mediating neuroprotection in excitotoxicity. They also reveal that previously-described neuroprotective effects of soluble TNF (and therefore TNFR1) against glutamate excitotoxicity in vitro are indirect, and mediated by astrocyte transmembrane TNF-neuron TNFR2 interactions. These results consolidate the concept that selective inhibition of soluble TNF/TNFR1 with maintenance of TNFR2 function would have anti-in ammatory and neuroprotective properties required for the safe treatment of CNS disease.
Co-modulation of TNFR1 and TNFR2 in an animal model of multiple sclerosis
Journal of Neuroinflammation, 2023
Background Tumour necrosis factor (TNF) is a pleiotropic cytokine and master regulator of the immune system. It acts through two receptors resulting in often opposing biological effects, which may explain the lack of therapeutic potential obtained so far in multiple sclerosis (MS) with non-receptor-specific anti-TNF therapeutics. Under neuroinflammatory conditions, such as MS, TNF receptor-1 (TNFR1) is believed to mediate the pro-inflammatory activities associated with TNF, whereas TNF receptor-2 (TNFR2) may instead induce anti-inflammatory effects as well as promote remyelination and neuroprotection. In this study, we have investigated the therapeutic potential of blocking TNFR1 whilst simultaneously stimulating TNFR2 in a mouse model of MS. Methods Experimental autoimmune encephalomyelitis (EAE) was induced with myelin oligodendrocyte glycoprotein (MOG 35-55) in humanized TNFR1 knock-in mice. These were treated with a human-specific TNFR1-selective antagonistic antibody (H398) and a mouse-specific TNFR2 agonist (EHD2-sc-mTNF R2), both in combination and individually. Histopathological analysis of spinal cords was performed to investigate demyelination and inflammatory infiltration, as well as axonal and neuronal degeneration. Retinas were examined for any protective effects on retinal ganglion cell (RGC) degeneration and neuroprotective signalling pathways analysed by Western blotting. Results TNFR modulation successfully ameliorated symptoms of EAE and reduced demyelination, inflammatory infiltration and axonal degeneration. Furthermore, the combinatorial approach of blocking TNFR1 and stimulating TNFR2 signalling increased RGC survival and promoted the phosphorylation of Akt and NF-κB, both known to mediate neuroprotection. Conclusion These results further support the potential of regulating the balance of TNFR signalling, through the co-modulation of TNFR1 and TNFR2 activity, as a novel therapeutic approach in treating inflammatory demyelinating disease.
Brain, 2000
In this review we summarize the essential findings about the function of tumour necrosis factor (TNF) and its cognate receptors TNFR1 and TNFR2, and lymphotoxin α (LT-α) ligands in immune-mediated CNS inflammation and demyelination. The advent of homologous recombination technology in rodents provides a new method which has been used during the last 5 years and has led to insights into the pathophysiology of experimental autoimmune encephalomyelitis (EAE) in an unprecedented way. Studies with knockout mice in which Keywords: tumour necrosis factor α; tumour necrosis factor α receptor type 1; demyelination; inflammation; experimental autoimmune encephalomyelitis Abbreviations: EAE ϭ experimental autoimmune encephalomyelitis; IL ϭ interleukin; IFN ϭ interferon; LT ϭ lymphotoxin; MBP ϭ myelin basic protein; MOG ϭ myelin oligodendrocyte glycoprotein; TNF ϭ tumour necrosis factor; TNFR ϭ TNF receptor by guest on May 31, 2013 http://brain.oxfordjournals.org/ Downloaded from Are TNF-α, LT-α or both cytokines required for EAE? In C57BL/6 mice, sensitization with MOG peptide 35-55 leads to a chronic relapsing inflammatory demyelinating by guest on May 31, 2013 http://brain.oxfordjournals.org/ Downloaded from by guest on May 31, 2013 http://brain.oxfordjournals.org/ Downloaded from Cope AP, Liblau RS, Yang XD, Congia M, Laudanna C, Schreiber RD, et al. Chronic tumor necrosis factor alters T cell responses by attenuating T cell receptor signaling. J Exp Med 1997; 185: 1573-84. Crisi GM, Santambrogio L, Hochwald GM, Smith SR, Carlino JA, Thorbecke GJ. Staphylococcal enterotoxin B and tumor-necrosis factor-alpha-induced relapses of experimental allergic encephalomyelitis: protection by transforming growth factor-beta and interleukin-10. Eur J Immunol 1995; 25: 3035-40. by guest on May 31, 2013 http://brain.oxfordjournals.org/ Downloaded from Juedes AE, Hjelmstrom P, Bergman CM, Neild AL, Ruddle NH. Kinetics and cellular origin of cytokines in the central nervous system: insight into mechanisms of myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis.
Journal of Neuroinflammation
Background During inflammatory demyelination, TNF receptor 1 (TNFR1) mediates detrimental proinflammatory effects of soluble TNF (solTNF), whereas TNFR2 mediates beneficial effects of transmembrane TNF (tmTNF) through oligodendroglia, microglia, and possibly other cell types. This model supports the use of selective inhibitors of solTNF/TNFR1 as anti-inflammatory drugs for central nervous system (CNS) diseases. A potential obstacle is the neuroprotective effect of solTNF pretreatment described in cultured neurons, but the relevance in vivo is unknown. Methods To address this question, we generated mice with neuron-specific depletion of TNFR1, TNFR2, or inhibitor of NF-κB kinase subunit β (IKKβ), a main downstream mediator of TNFR signaling, and applied experimental models of inflammatory demyelination and acute and preconditioning glutamate excitotoxicity. We also investigated the molecular and cellular requirements of solTNF neuroprotection by generating astrocyte-neuron co-culture...
Selective Modulation of TNF–TNFRs Signaling: Insights for Multiple Sclerosis Treatment
Frontiers in Immunology
Autoimmunity develops when self-tolerance mechanisms are failing to protect healthy tissue. A sustained reaction to self is generated, which includes the generation of effector cells and molecules that destroy tissues. A way to restore this intrinsic tolerance is through immune modulation that aims at refurbishing this immunologically naïve or unresponsive state, thereby decreasing the aberrant immune reaction taking place. One major cytokine has been shown to play a pivotal role in several autoimmune diseases such as rheumatoid arthritis (RA) and multiple sclerosis (MS): tumor necrosis factor alpha (TNFα) modulates the induction and maintenance of an inflammatory process and it comes in two variants, soluble TNF (solTNF) and transmembrane bound TNF (tmTNF). tmTNF signals via TNFR1 and TNFR2, whereas solTNF signals mainly via TNFR1. TNFR1 is widely expressed and promotes mainly inflammation and apoptosis. Conversely, TNFR2 is restricted mainly to immune and endothelial cells and it is known to activate the pro-survival PI3K-Akt/PKB signaling pathway and to sustain regulatory T cells function. Anti-TNFα therapies are successfully used to treat diseases such as RA, colitis, and psoriasis. However, clinical studies with a non-selective inhibitor of TNFα in MS patients had to be halted due to exacerbation of clinical symptoms. One possible explanation for this failure is the non-selectivity of the treatment, which avoids TNFR2 stimulation and its immune and tissue protective properties. Thus, a receptor-selective modulation of TNFα signal pathways provides a novel therapeutic concept that might lead to new insights in MS pathology with major implications for its effective treatment.
Anti-TNFR1 targeting in humanized mice ameliorates disease in a model of multiple sclerosis
Journal of Neuroimmunology, 2014
Tumour necrosis factor (TNF) signalling is mediated via two receptors, TNF-receptor 1 (TNFR1) and TNF-receptor 2 (TNFR2), which work antithetically to balance CNS immune responses involved in autoimmune diseases such as multiple sclerosis. To determine the therapeutic potential of selectively inhibiting TNFR1 in mice with experimental autoimmune encephalomyelitis, we used chimeric human/ mouse TNFR1 knock-in mice allowing the evaluation of antagonistic anti-human TNFR1 antibody efficacy. Treatment of mice after onset of disease with ATROSAB resulted in a robust amelioration of disease severity, correlating with reduced central nervous system immune cell infiltration. Long-term efficacy of treatment was achieved by treatment with the parental mouse anti-human TNFR1 antibody, H398, and extended by subsequent re-treatment of mice following relapse. Our data support the hypothesis that anti-TNFR1 therapy restricts immune cell infiltration across the blood-brain barrier through the down-regulation of TNF-induced adhesion molecules, rather than altering immune cell composition or activity. Collectively, we demonstrate the potential for anti-human TNFR1 therapies to effectively modulate immune responses in autoimmune disease.
Antibody-Mediated Inhibition of TNFR1 Attenuates Disease in a Mouse Model of Multiple Sclerosis
PLoS ONE, 2014
Tumour necrosis factor (TNF) is a proinflammatory cytokine that is known to regulate inflammation in a number of autoimmune diseases, including multiple sclerosis (MS). Although targeting of TNF in models of MS has been successful, the pathological role of TNF in MS remains unclear due to clinical trials where the non-selective inhibition of TNF resulted in exacerbated disease. Subsequent experiments have indicated that this may have resulted from the divergent effects of the two TNF receptors, TNFR1 and TNFR2. Here we show that the selective targeting of TNFR1 with an antagonistic antibody ameliorates symptoms of the most common animal model of MS, experimental autoimmune encephalomyelitis (EAE), when given following both a prophylactic and therapeutic treatment regime. Our results demonstrate that antagonistic TNFR1specific antibodies may represent a therapeutic approach for the treatment of MS in the future.