We have previously shown that two tumor necrosis factor (TNF) receptors (TNFR) exhibit antagonistic functions during neurodegenerative processes in vivo with TNFR1 aggravating and TNFR2 reducing neuronal cell loss, respectively. To elucidate the neuroprotective signaling pathways of TNFR2, we investigated glutamateinduced excitotoxicity in primary cortical neurons. TNFexpressing neurons from TNF-transgenic mice were found to be strongly protected from glutamate-induced apoptosis. Neurons from wild type and TNFR1 ؊/؊ mice prestimulated with TNF or agonistic TNFR2-specific antibodies were also resistant to excitotoxicity, whereas TNFR2 ؊/؊ neurons died upon glutamate and/or TNF exposures. Both protein kinase B/Akt and nuclear factor-B (NF-B) activation were apparent upon TNF treatment. Both TNFR1 and TNFR2 induced the NF-B pathway, yet with distinguishable kinetics and upstream activating components, TNFR1 only induced transient NF-B activation, whereas TNFR2 facilitated long term phosphatidylinositol 3-kinase-dependent NF-B activation strictly. Glutamate-induced triggering of the ionotropic N-methyl-Daspartate receptor was required for the enhanced and persistent phosphatidylinositol 3-kinase-dependent NF-B activation by TNFR2, indicating a positive cooperation of TNF and neurotransmitter-induced signal pathways. TNFR2-induced persistent NF-B activity was essential for neuronal survival. Thus, the duration of NF-B activation is a critical determinant for sensitivity toward excitotoxic stress and is dependent on a differential upstream signal pathway usage of the two TNFRs. Tumor necrosis factor (TNF)1 is a prominent proinflammatory mediator that has been causally associated with the pathophysiology of several acute and chronic diseases, in particular rheumatoid arthritis and Morbus Crohn (1, 2). Up-regulated TNF expression has also been found in various neurodegenerative diseases such as cerebral malaria, AIDS dementia, Alzheimer's disease, multiple sclerosis, and stroke, suggesting a potential pathogenic role of TNF in these diseases as well (3-7). The membrane-expressed form of TNF signals through both TNF receptors (TNFR1 and TNFR2), whereas soluble TNF proteolytically cleaved from the membrane form acts mainly via TNFR1 (8). Signal pathways initiated from the death domain-containing TNFR1, leading to both proapoptotic and antiapoptotic cellular responses, have been studied in great detail (9). In contrast, there is less information regarding the molecular mechanisms surrounding signal pathways and cellular responses solely initiated via TNFR2 because of concomitant TNFR1 signals in normal situations. The evaluation of the physiological role of TNFR2 by large depends on data obtained from TNFR1 Ϫ/Ϫ mice. We have recently investigated the role of TNF and its receptors in retinal ischemia and unraveled an antagonistic function of TNFR1 and TNFR2. TNFR2 exerts neuroprotection in a phosphatidylinositol 3-kinase (PI3K) dependent manner, which is counterbalanced by the neurodegenerative action of TNFR1 (10). TNFR1 h...

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Alzheimer's disease (AD) is associated with an altered immune response, resulting in chronic increased inflammatory cytokine production with a prominent role of TNF-α. TNF-α signals are mediated by two receptors: TNF receptor 1 (TNFR1) and TNF receptor 2 (TNFR2). Signaling through TNFR2 is associated with neuroprotection, whereas signaling through TNFR1 is generally proinflammatory and proapoptotic. Here, we have identified a TNF-α-induced proinflammatory agent, lipocalin 2 (Lcn2) via gene array in murine primary cortical neurons. Further investigation showed that Lcn2 protein production and secretion were activated solely upon TNFR1 stimulation when primary murine neurons, astrocytes, and microglia were treated with TNFR1 and TNFR2 agonistic antibodies. Lcn2 was found to be significantly decreased in CSF of human patients with mild cognitive impairment and AD and increased in brain regions associated with AD pathology in human postmortem brain tissue. Mechanistic studies in cultures of primary cortical neurons showed that Lcn2 sensitizes nerve cells to β-amyloid toxicity. Moreover, Lcn2 silences a TNFR2-mediated protective neuronal signaling cascade in neurons, pivotal for TNF-α-mediated neuroprotection. The present study introduces Lcn2 as a molecular actor in neuroinflammation in early clinical stages of AD.

Extensive research has been performed to unravel the mechanistic signaling pathways mediated by tumor necrosis factor receptor 1 (TNFR1), by contrast there is limited knowledge on cellular signaling upon activation of TNFR2. Recently published data have revealed that these two receptors not only function independently, but also can influence each other via cross‐talk between the different signaling pathways initiated by TNFR1 and TNFR2 stimulation. Furthermore, the complexity of this cross‐talk is also dependent on the different signaling kinetics between TNFR1 and TNFR2, by which a delicate balance between cell survival and apoptosis can be maintained. Some known signaling factors and the kinetics that are involved in the receptor cross‐talk between TNFR1 and TNFR2 are the topic of this review.

Despite the recognized role of tumor necrosis factor (TNF) in inflammation and neuronal degeneration, anti-TNF therapeutics failed to treat neurodegenerative diseases. Animal disease models had revealed the antithetic effects of the two TNF receptors (TNFR) in the central nervous system, whereby TNFR1 has been associated with inflammatory degeneration and TNFR2 with neuroprotection. We here show the therapeutic potential of selective inhibition of TNFR1 and activation of TNFR2 by ATROSAB, a TNFR1-selective antagonistic antibody, and EHD2-scTNF R2 , an agonistic TNFR2-selective TNF, respectively, in a mouse model of NMDA-induced acute neurodegeneration. Coadministration of either ATROSAB or EHD2-scTNF R2 into the magnocellular nucleus basalis significantly protected cholinergic neurons and their cortical projections against cell death, and reverted the neurodegeneration-associated memory impairment in a passive avoidance paradigm. Simultaneous blocking of TNFR1 and TNFR2 signaling, however, abrogated the therapeutic effect. Our results uncover an essential role of TNFR2 in neuroprotection. Accordingly, the therapeutic activity of ATROSAB is mediated by shifting the balance of the antithetic activity of endogenous TNF toward TNFR2, which appears essential for neuroprotection. Our data also explain earlier results showing that complete blocking of TNF activity by anti-TNF drugs was detrimental rather than protective and argue for the use of next-generation TNFR-selective TNF therapeutics as an effective approach in treating neurodegenerative diseases.

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Sickness behavior and cognitive dysfunction occur frequently by unknown mechanisms in virus-infected individuals with malignancies treated with type I interferons (IFNs) and in patients with autoimmune disorders. We found that during sickness behavior, single-stranded RNA viruses, double-stranded RNA ligands, and IFNs shared pathways involving engagement of melanoma differentiation-associated protein 5 (MDA5), retinoic acid-inducible gene 1 (RIG-I), and mitochondrial antiviral signaling protein (MAVS), and subsequently induced IFN responses specifically in brain endothelia and epithelia of mice. Behavioral alterations were specifically dependent on brain endothelial and epithelial IFN receptor chain 1 (IFNAR). Using gene profiling, we identified that the endothelia-derived chemokine ligand CXCL10 mediated behavioral changes through impairment of synaptic plasticity. These results identified brain endothelial and epithelial cells as natural gatekeepers for virus-induced sickness behavior, demonstrated tissue specific IFNAR engagement, and established the CXCL10-CXCR3 axis as target for the treatment of behavioral changes during virus infection and type I IFN therapy.