β-Catenin–dependent lysosomal targeting of internalized tumor necrosis factor-α suppresses caspase-8 activation in apoptosis-resistant colon cancer cells

Abstract

Tumor necrosis factor-α (TNF)-induced apoptotic activation of caspase-8 requires internalization of its receptor. This study shows that constitutively activated β-catenin is required to facilitate the lysosomal delivery of internalized TNF, the inhibition of caspase-8 activation, and the suppression of apoptosis in colon cancer cells.

Prostaglandin signaling suppresses beneficial microglial function in Alzheimer’s disease models

“…Microglial genes associated with AD include CD33 (5-7), TREM2 (8,9), and CR1 (10,11); together with additional studies (12), these findings are indicative of an important role of microglia in maintaining local brain homeostasis and preventing Aβ 42 -mediated synaptic and inflammatory injury. Notably, clearance of accumulating Aβ 42 is dependent on effective sensing by microglia (mediated by chemokines), followed by Aβ 42 degradation.…”

“…Microglial genes associated with AD include CD33 (5-7), TREM2 (8,9), and CR1 (10,11); together with additional studies (12), these findings are indicative of an important role of microglia in maintaining local brain homeostasis and preventing Aβ 42 -mediated synaptic and inflammatory injury. Notably, clearance of accumulating Aβ 42 is dependent on effective sensing by microglia (mediated by chemokines), followed by Aβ 42 degradation. Moreover, prolonged exposure to proinflammatory cytokines or accumulating Aβ 42 peptides cause microglia to lose their normal abilities to clear toxic proteins and control inflammation (13,14), a detrimental phenotype in the context of age-associated Aβ 42 accumulation.…”

“…induced a robust inflammatory transcriptional response in aged but not young macrophages that was further increased by costimulation with 1 μM butaprost ( Figure 1B). Aβ 42 -induced increases in IL-1β generation and secretion were further amplified with butaprost ( Figure 1C and Supplemental Figure 1A; supplemental material available online with this article; doi:10.1172/JCI77487DS1), which suggests that myeloid EP2 signaling increases inflammasome generation of IL-1β. Conversely, expression of the chemokines MCP-1 and MIP-1α, which are involved in myeloid cell recruitment to sites of injury, was suppressed with butaprost both basally and with Aβ 42 stimulation ( Figure 1D and Supplemental Figure 1, B and C).…”

“…The widely considered "amyloid hypothesis" of AD causation posits that accumulation of amyloid β 42 (Aβ 42 ) triggers inflammation, tau hyperphosphorylation, and synaptic and neuronal loss, leading to cognitive decline (2,3). Recent studies, however, indicate that brain Aβ 42 accumulates in subjects that do not exhibit dementia, which suggests that Aβ 42 accumulation may be necessary but not sufficient for development of cognitive impairment (4) and that additional factors are required to tip the balance toward progression to AD dementia.…”

“…Notably, clearance of accumulating Aβ 42 is dependent on effective sensing by microglia (mediated by chemokines), followed by Aβ 42 degradation. Moreover, prolonged exposure to proinflammatory cytokines or accumulating Aβ 42 peptides cause microglia to lose their normal abilities to clear toxic proteins and control inflammation (13,14), a detrimental phenotype in the context of age-associated Aβ 42 accumulation. Thus, microglia are emerging as critical regulators of innate immune responses in AD and, more broadly, in other neurodegenerative disorders, and understanding the molecular and cellular mechanisms that cause microglial dysfunction may help identify strategies to restore healthy microglial function and prevent development of AD.…”