TNF signaling inhibition in the CNS: implications for normal brain function and neurodegenerative disease

Abstract

The role of tumor necrosis factor (TNF) as an immune mediator has long been appreciated but its function in the brain is still unclear. TNF receptor 1 (TNFR1) is expressed in most cell types, and can be activated by binding of either soluble TNF (solTNF) or transmembrane TNF (tmTNF), with a preference for solTNF; whereas TNFR2 is expressed primarily by microglia and endothelial cells and is preferentially activated by tmTNF. Elevation of solTNF is a hallmark of acute and chronic neuroinflammation as well as a number of neurodegenerative conditions including ischemic stroke, Alzheimer's (AD), Parkinson's (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). The presence of this potent inflammatory factor at sites of injury implicates it as a mediator of neuronal damage and disease pathogenesis, making TNF an attractive target for therapeutic development to treat acute and chronic neurodegenerative conditions. However, new and old observations from animal models and clinical trials reviewed here suggest solTNF and tmTNF exert different functions under normal and pathological conditions in the CNS. A potential role for TNF in synaptic scaling and hippocampal neurogenesis demonstrated by recent studies suggest additional in-depth mechanistic studies are warranted to delineate the distinct functions of the two TNF ligands in different parts of the brain prior to large-scale development of anti-TNF therapies in the CNS. If inactivation of TNF-dependent inflammation in the brain is warranted by additional preclinical studies, selective targeting of TNFR1-mediated signaling while sparing TNFR2 activation may lessen adverse effects of anti-TNF therapies in the CNS.

PI3Kδ inhibition reduces TNF secretion and neuroinflammation in a mouse cerebral stroke model

“…Astrocytes also produce and release TNF but they are not sensitive to PI3Kd inhibition in vitro as they do not exhibit PI3Kd immunoreactivity, suggesting different trafficking regulators might control TNF release in these cells. The lack of PI3Kd detection in astrocytes in vitro indicates that the observed decrease in astrocytic TNF in vivo under I/R may result from attenuated proinflammatory feedback cascades 5,43,44 stemming from reduced microglial TNF secretion. Our study is in good agreement with other studies pointing to a key role of microglial TNF in early-phase inflammation in the CNS 13 .…”

Body mass and cognitive decline are indirectly associated via inflammation among aging adults

“…Inflammatory models of neurodegeneration propose that systemic inflammation is negatively associated with cognition via increases in neuro-inflammation. Inflammatory cytokines -including Tumor Necrosis Factor(TNF)α, Interleukin(IL)-1β, and IL-6 -secreted by microglia in the brain likely establish and maintain neuro-inflammation (Glass, Saijo, Winner, Marchetto, & Gage, 2010), which can leads to neuronal apoptosis over the long-term (McCoy & Tansey, 2008;Simi, Tsakiri, Wang, & Rothwell, 2007), and inhibits neurogenesis in adults (Ekdahl, Claasen, Bonde, Kokaia, & Lindvall, 2003). Systemic inflammation in the periphery is tied to neuro-inflammation in neurodegenerative disorders (Perry, 2004), as well as in aging populations more generally (Perry, 2010).…”

The Physiological Role of Tumor Necrosis Factor in Human Immunity and Its Potential Implications in Spinal Manipulative Therapy: A Narrative Literature Review

“…[17][18][19][20] TNF also plays an essential beneficial role in a variety of physiological functions including immune surveillance, sleep regulation, synaptic scaling, and neurogenesis. [33][34][35][36][37][38] TNF was initially recognized for its ability to kill tumor cells without harming normal cells. 11 In addition to confirming this antitumor capacity, [12][13][14] early studies also reported that TNF was essential in anti-infection.…”