Developmental synaptic regulator, TWEAK/Fn14 signaling, is a determinant of synaptic function in models of stroke and neurodegeneration

Nagy, Dávid; Ennis, Katelin A.; Wei, Ru; Su, Susan C.; Hinckley, Christopher A.; Gu, Rong-Fang; Gao, Benbo; Massol, Ramiro; Ehrenfels, Chris; Jandreski, Luke; Thomas, Ankur; Nelson, Ashley N.; Gyoneva, Stefka; Hajós, Mihály; Burkly, Linda C.

doi:10.1073/pnas.2001679118

Cited by 25 publications

(27 citation statements)

References 50 publications

(58 reference statements)

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“…This leads to the complement-mediated, inappropriate phagocytosis of functional synapses by microglia resulting in disease-linked synapse loss and cognitive decline ( 50 ). Similarly, inhibiting TWEAK-Fn14 signaling in an AD mouse model ameliorated deficits in synapse plasticity in the hippocampus, suggesting that multiple immune pathways can contribute to the same pathological conditions that affect neural connectivity ( 69 ). In a mouse model of MS, where synapse loss in grey matter regions precedes axonal degeneration (independent of demyelination) ( 87 ), genetic deletion of C3 can ameliorate both microglial activation as well as neural dysfunction ( 88 ) suggesting that targeting the complement system may have therapeutic potential for treating chronic neuroinflammatory illnesses before symptoms arise.…”

Section: Discussion: Broader Impacts and New Horizonsmentioning

confidence: 99%

“…Whereas ccc and IL-33 signaling play varied roles across multiple neural circuits, until recently it was not known whether TWEAK-Fn14 signaling extends beyond the retinogeniculate synapse to remodel other circuits during development or in the adult, and whether this pathway may also be relevant to disease. A recent study by Nagy et al ( 69 ) showed that exogenous application of recombinant TWEAK dampens long-term potentiation, a measure of activity-dependent synaptic strengthening, in the hippocampus. Moreover, suppression of endogenous TWEAK using blocking antibodies ameliorated Fn14-dependent synaptic deficits in mouse models of stroke and Alzheimer's disease, indicating not only that the TWEAK-Fn14 pathway is an important synaptic organizer across multiple circuits in the brain but also that disruptions in TWEAK-Fn14 signaling may contribute to neurological dysfunction related to brain disorders.…”

Section: Cytokine Signaling In Neurodevelopmental Processes Shaped By Activitymentioning

confidence: 99%

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Microglia, Cytokines, and Neural Activity: Unexpected Interactions in Brain Development and Function

Ferro

Auguste²,

Cheadle³

2021

Front. Immunol.

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Intercellular signaling molecules such as cytokines and their receptors enable immune cells to communicate with one another and their surrounding microenvironments. Emerging evidence suggests that the same signaling pathways that regulate inflammatory responses to injury and disease outside of the brain also play powerful roles in brain development, plasticity, and function. These observations raise the question of how the same signaling molecules can play such distinct roles in peripheral tissues compared to the central nervous system, a system previously thought to be largely protected from inflammatory signaling. Here, we review evidence that the specialized roles of immune signaling molecules such as cytokines in the brain are to a large extent shaped by neural activity, a key feature of the brain that reflects active communication between neurons at synapses. We discuss the known mechanisms through which microglia, the resident immune cells of the brain, respond to increases and decreases in activity by engaging classical inflammatory signaling cascades to assemble, remodel, and eliminate synapses across the lifespan. We integrate evidence from (1) in vivo imaging studies of microglia-neuron interactions, (2) developmental studies across multiple neural circuits, and (3) molecular studies of activity-dependent gene expression in microglia and neurons to highlight the specific roles of activity in defining immune pathway function in the brain. Given that the repurposing of signaling pathways across different tissues may be an important evolutionary strategy to overcome the limited size of the genome, understanding how cytokine function is established and maintained in the brain could lead to key insights into neurological health and disease.

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Section: Discussion: Broader Impacts and New Horizonsmentioning

confidence: 99%

Section: Cytokine Signaling In Neurodevelopmental Processes Shaped By Activitymentioning

confidence: 99%

Microglia, Cytokines, and Neural Activity: Unexpected Interactions in Brain Development and Function

Ferro

Auguste²,

Cheadle³

2021

Front. Immunol.

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“…The role of TWEAK/Fn14 outside of synapses is however, poorly understood. In the study by Nagy et al it was demonstrated that inhibition of TWEAK/Fn14 is beneficial post ischemic stroke as it appears to limit synaptic degradation and increase basal synaptic transmission and plasticity in Fn14KD mice [5]. Other cytokines such as IL1β and TNFα can also be found at the site of injury post ischemic stroke [113].…”

Section: Tweak and Cardiovascular Diseasementioning

confidence: 99%

“…There is growing evidence of direct TWEAK/Fn14/CD163 involvement in several autoinflammatory pathologies across several tissue and cell types; however, the exact impact of TWEAK/Fn14/ CD163 on disease development remains poorly understood. Recently, new functions for the TWEAK/Fn14/CD163 axis have become apparent, including the control of synaptic transmission and formation of atherosclerotic plaques [4,5]. Here, we review the latest understanding of TWEAK/Fn14/ CD163 as one of the chief regulators in immune signalling and its cell-specific role in metabolic disease development and progression.…”

Section: Introductionmentioning

confidence: 99%

The TWEAK/Fn14/CD163 axis—implications for metabolic disease

Ratajczak

Atkinson

Kelly

2021

Rev Endocr Metab Disord

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TWEAK (tumor necrosis factor-like weak inducer of apoptosis) is a member of the TNF superfamily that controls a multitude of cellular events including proliferation, migration, differentiation, apoptosis, angiogenesis, and inflammation. TWEAK control of these events is via an expanding list of intracellular signalling pathways which include NF-κB, ERK/MAPK, Notch, EGFR and AP-1. Two receptors have been identified for TWEAK – Fn14, which targets the membrane bound form of TWEAK, and CD163, which scavenges the soluble form of TWEAK. TWEAK appears to elicit specific events based on the receptor to which it binds, tissue type in which it is expressed, specific extrinsic conditions, and the presence of other cytokines. TWEAK signalling is protective in healthy tissues, but in chronic inflammatory states become detrimental to the tissue. Consistent data show a role for the TWEAK/FN14/CD163 axis in metabolic disease, chronic autoimmune diseases, and acute ischaemic stroke. Low circulating concentrations of soluble TWEAK are predictive of poor cardiovascular outcomes in those with and without diabetes. This review details the current understanding of the TWEAK/Fn14/CD163 axis as one of the chief regulators of immune signalling and its cell-specific role in metabolic disease development and progression.

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“…Fn14 has only one known ligand, a cytokine named TWEAK (tumor necrosis factor-like weak inducer of apoptosis), and has been shown to be a stress-response gene in many tissues (Muñoz-García et al, 2006;Nagy et al, 2021;Peng et al, 2018;Unudurthi et al, 2020;Zhao et al, 2007).…”

Section: Differentiating Urothelial Cells Initiate Cell Death Independent Of Failed Stratificationmentioning

confidence: 99%

Exocyst Inactivation in Urothelial Cells Disrupts Autophagy and Activates non-canonical NF-κB

Ortega

Villiger

Harrison-Chau

et al. 2021

Preprint

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Ureter obstruction is a highly prevalent event during embryonic development and is a major cause of pediatric kidney disease. We have reported that ureteric bud specific ablation of the exocyst Exoc5 subunit in late murine gestation results in failure of urothelial stratification, cell death, and complete ureter obstruction. However, the mechanistic connection between disrupted exocyst activity, urothelial cell death, and subsequent ureter obstruction was unclear. Here, we report that inhibited urothelial stratification does not drive cell death during ureter development. Instead, we demonstrate that the exocyst plays a critical role in autophagy in urothelial cells, and that disruption of autophagy activates a urothelial NF-κB stress response. Impaired autophagy first provokes canonical NF κB activity which is progressively followed by increasing non-canonical NF-κB activity and cell death if the stress remains unresolved. Furthermore, we demonstrate that ureter obstructions can be completely rescued in Exoc5 conditional knockout mice by administering a single dose of pan-caspase inhibitor z VAD-FMK at E16.5 prior to urothelial cell death. Taken together, ablation of Exoc5 disrupts autophagic stress response and activates progressive NF-κB signaling which promotes obstructive uropathy.

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Developmental synaptic regulator, TWEAK/Fn14 signaling, is a determinant of synaptic function in models of stroke and neurodegeneration

Cited by 25 publications

References 50 publications

Microglia, Cytokines, and Neural Activity: Unexpected Interactions in Brain Development and Function

Microglia, Cytokines, and Neural Activity: Unexpected Interactions in Brain Development and Function

The TWEAK/Fn14/CD163 axis—implications for metabolic disease

Exocyst Inactivation in Urothelial Cells Disrupts Autophagy and Activates non-canonical NF-κB

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