Activation of TNF receptor 2 in microglia promotes induction of anti-inflammatory pathways

Veroni, Caterina; Gabriele, Lucia; Canini, Irene; Castiello, Luciano; Coccia, Eliana M.; Remoli, Maria Elena; Columba-Cabezas, Sandra; Aricò, Eleonora; Aloisi, Francesca; Agresti, Cristina

doi:10.1016/j.mcn.2010.06.014

Cited by 97 publications

(74 citation statements)

References 71 publications

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“…Accordingly, sTNF and mTNF can exert specific and counteracting functions under normal and pathological conditions (36,64), and distinct TNFR-mediated signaling pathways balance specific immune responses and neurobiological functions (4,6,11,43,51,72,74). Despite the central roles of TNFRs in the regulation of TNF responses, the underlying molecular mechanisms determining receptor responsiveness have long remained unresolved.…”

Section: Discussionmentioning

confidence: 99%

The Tumor Necrosis Factor Receptor Stalk Regions Define Responsiveness to Soluble versus Membrane-Bound Ligand

Richter

Messerschmidt

Holeiter

et al. 2012

Molecular and Cellular Biology

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The family of tumor necrosis factor receptors (TNFRs) and their ligands form a regulatory signaling network that controls immune responses. Various members of this receptor family respond differently to the soluble and membrane-bound forms of their respective ligands. However, the determining factors and underlying molecular mechanisms of this diversity are not yet understood. Using an established system of chimeric TNFRs and novel ligand variants mimicking the bioactivity of membranebound TNF (mTNF), we demonstrate that the membrane-proximal extracellular stalk regions of TNFR1 and TNFR2 are crucial in controlling responsiveness to soluble TNF (sTNF). We show that the stalk region of TNFR2, in contrast to the corresponding part of TNFR1, efficiently inhibits both the receptor's enrichment/clustering in particular cell membrane regions and ligandindependent homotypic receptor preassembly, thereby preventing sTNF-induced, but not mTNF-induced, signaling. Thus, the stalk regions of the two TNFRs not only have implications for additional TNFR family members, but also provide potential targets for therapeutic intervention.

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Section: Discussionmentioning

confidence: 99%

The Tumor Necrosis Factor Receptor Stalk Regions Define Responsiveness to Soluble versus Membrane-Bound Ligand

Richter

Messerschmidt

Holeiter

et al. 2012

Molecular and Cellular Biology

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“…More recent studies have revealed a protective potential for TNFα in the retina, possibly mediated through TNFR2, 81,118 and contrary to the model of secondary degeneration. In a crush paradigm, when TNFα is delivered prior to injury, RGC survival increased after optic nerve trauma, while TNFα-deficient mice exhibited greater RGC loss after crush, implicating a protective role for this cytokine.…”

Section: Impact Of Inflammatory Responses On the Retinamentioning

confidence: 98%

Neuroinflammation in Glaucoma and Optic Nerve Damage

Nair¹,

Nickells²

2015

Progress in Molecular Biology and Translational Science

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“…Moreover, its levels were found downregulated in the Tg2576 AD mouse model, and reduced CXCL12 levels were shown to cause impairments in learning and memory [212]. Lastly, TNFR2 signaling in microglia has been related with the induction of anti-inflammatory pathways, for example the upregulation of IL-10 [213].…”

Section: Tnfr2-possible Downstream Targets In Neurodegenerationmentioning

confidence: 99%

“…Indeed, different studies have suggested that TNF-α signaling may be strongly brain region-specific, which may in part depend on, e.g., the relative density and activity of microglia in specific regions [213,215,216]. Also, the timing of TNF-α signaling in different stages of neurodegeneration could affect the outcomes of TNF-α.…”

Section: Complex Matters: Tnfr1 Signaling Is Primarily Damaging and Tmentioning

confidence: 99%

Targeting of Tumor Necrosis Factor Alpha Receptors as a Therapeutic Strategy for Neurodegenerative Disorders

et al. 2015

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Numerous studies have revealed the pleiotropic functions of tumor necrosis factor alpha (TNF-α), and have linked it with several neurodegenerative disorders. This review describes the signaling pathways induced by TNF-α via its two receptors (TNFR1 and TNFR2), and their functions in neurodegenerative processes as in Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and ischemic stroke. It has become clear that TNF-α may exert divergent actions in neurodegenerative disorders, including neurodegenerative and neuroprotective effects, which appear to depend on its signaling via either TNFR1 or TNFR2. Specific targeting of these receptors is a promising therapeutic strategy for many disorders.

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Activation of TNF receptor 2 in microglia promotes induction of anti-inflammatory pathways

Cited by 97 publications

References 71 publications

The Tumor Necrosis Factor Receptor Stalk Regions Define Responsiveness to Soluble versus Membrane-Bound Ligand

The Tumor Necrosis Factor Receptor Stalk Regions Define Responsiveness to Soluble versus Membrane-Bound Ligand

Neuroinflammation in Glaucoma and Optic Nerve Damage

Targeting of Tumor Necrosis Factor Alpha Receptors as a Therapeutic Strategy for Neurodegenerative Disorders

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