Oligodendrocytes modulate the immune-inflammatory response in EAE via TNFR2 signaling

Madsen, Pernille M.; Desu, Haritha L.; Vaccari, Juan Pablo de Rivero; Florimon, Yoleinny; Ellman, Ditte Gry; Keane, Robert W.; Clausen, Bettina Hjelm; Lambertsen, Kate Lykke; Brambilla, Roberta

doi:10.1016/j.bbi.2019.11.017

Cited by 54 publications

(58 citation statements)

References 63 publications

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“…Interestingly, recent work using the same animals showed that oligodendrocyte-TNFR2 not only promotes myelination, but also modulates the immune-inflammatory response in the early phase of EAE pathogenesis. In particular, specific ablation of oligodendroglial-TNFR2 resulted in increased microglia activation and blood brain barrier permeability, and accelerated infiltration of immune cells into the spinal cord prior to development of motor symptoms (Madsen et al, 2019). Further, opposing functions of microglial and macrophagic TNFR2 in the pathogenesis of EAE were reported.…”

Section: Degenerative Diseasesmentioning

confidence: 99%

Selective Targeting of TNF Receptors as a Novel Therapeutic Approach

Fischer

Kontermann

Pfizenmaier

2020

Front. Cell Dev. Biol.

151

146

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Tumor necrosis factor (TNF) is a central regulator of immunity. Due to its dominant proinflammatory effects, drugs that neutralize TNF were developed and are clinically used to treat inflammatory and autoimmune diseases, such as rheumatoid arthritis, inflammatory bowel disease and psoriasis. However, despite their clinical success the use of anti-TNF drugs is limited, in part due to unwanted, severe side effects and in some diseases its use even is contraindicative. With gaining knowledge about the signaling mechanisms of TNF and the differential role of the two TNF receptors (TNFR), alternative therapeutic concepts based on receptor selective intervention have led to the development of novel protein therapeutics targeting TNFR1 with antagonists and TNFR2 with agonists. These antibodies and bio-engineered ligands are currently in preclinical and early clinical stages of development. Preclinical data obtained in different disease models show that selective targeting of TNFRs has therapeutic potential and may be superior to global TNF blockade in several disease indications.

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Section: Degenerative Diseasesmentioning

confidence: 99%

Selective Targeting of TNF Receptors as a Novel Therapeutic Approach

Fischer

Kontermann

Pfizenmaier

2020

Front. Cell Dev. Biol.

151

146

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“…Table 1 details all identified mouse models in which TNFR1 and TNFR2 were assessed independently. In brief, neurologic models have demonstrated even more complex effects of selective TNFR deletion; in EAE, TNFR2 is protective on microglia but deleterious on monocytes and macrophages whereas TNFR1 appears harmful in all contexts due to reducing the blood brain barrier function against cell infiltration into the CNS ( 84 , 105 , 117 ). In mouse models of pain, deletion of TNFR1 lead to reduction of mechanical pain as well as NMDA activation of lamina II neurons ( 86 , 87 , 134 ).…”

Section: Differential Tnfr Activity In Mouse Modelsmentioning

confidence: 99%

Tumor Necrosis Factor Receptors: Pleiotropic Signaling Complexes and Their Differential Effects

2020

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Since its discovery in 1975, TNFα has been a subject of intense study as it plays significant roles in both immunity and cancer. Such attention is well deserved as TNFα is unique in its engagement of pleiotropic signaling via its two receptors: TNFR1 and TNFR2. Extensive research has yielded mechanistic insights into how a single cytokine can provoke a disparate range of cellular responses, from proliferation and survival to apoptosis and necrosis. Understanding the intracellular signaling pathways induced by this single cytokine via its two receptors is key to further revelation of its exact functions in the many disease states and immune responses in which it plays a role. In this review, we describe the signaling complexes formed by TNFR1 and TNFR2 that lead to each potential cellular response, namely, canonical and non-canonical NF-κB activation, apoptosis and necrosis. This is followed by a discussion of data from in vivo mouse and human studies to examine the differential impacts of TNFR1 versus TNFR2 signaling.

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“…Importantly, treatment of the EAE mutant mice with the solTNF inhibitor XPro1595 was ineffective in the recovery of the symptoms, indicating that tmTNF can exert its beneficial effects of oligodendrocytes only in the presence of TNFR2 [ 98 ]. Moreover, lack of TNFR2 in oligodendrocytes induces an early activation of microglia, an increased BBB permeability and infiltration of immune cells in the spinal cord, leading to an accelerated onset and a higher disability peak, and to an overall increased severity of EAE [ 125 ]. This suggests that TNFR2 signaling in oligodendrocytes exert an immune-inflammatory function in EAE.…”

Section: Evidence For Tnf Involvement In Pathological Hallmarks Ofmentioning

confidence: 99%

Re-Examining the Role of TNF in MS Pathogenesis and Therapy

Fresegna

Bullitta

Musella

et al. 2020

Cells

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Multiple sclerosis (MS) is a common neurological disorder of putative autoimmune origin. Clinical and experimental studies delineate abnormal expression of specific cytokines over the course of the disease. One major cytokine that has been shown to play a pivotal role in MS is tumor necrosis factor (TNF). TNF is a pleiotropic cytokine regulating many physiological and pathological functions of both the immune system and the central nervous system (CNS). Convincing evidence from studies in human and experimental MS have demonstrated the involvement of TNF in various pathological hallmarks of MS, including immune dysregulation, demyelination, synaptopathy and neuroinflammation. However, due to the complexity of TNF signaling, which includes two-ligands (soluble and transmembrane TNF) and two receptors, namely TNF receptor type-1 (TNFR1) and type-2 (TNFR2), and due to its cell- and context-differential expression, targeting the TNF system in MS is an ongoing challenge. This review summarizes the evidence on the pathophysiological role of TNF in MS and in different MS animal models, with a special focus on pharmacological treatment aimed at controlling the dysregulated TNF signaling in this neurological disorder.

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Oligodendrocytes modulate the immune-inflammatory response in EAE via TNFR2 signaling

Cited by 54 publications

References 63 publications

Selective Targeting of TNF Receptors as a Novel Therapeutic Approach

Selective Targeting of TNF Receptors as a Novel Therapeutic Approach

Tumor Necrosis Factor Receptors: Pleiotropic Signaling Complexes and Their Differential Effects

Re-Examining the Role of TNF in MS Pathogenesis and Therapy

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