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γ-Tocopherol attenuates COPD-associated macrophage inflammation through the PSEN1–SYT7–PI3K/Akt axis

ABSTRACT: Rationale: Chronic obstructive pulmonary disease (COPD) features persistent airway inflammation, oxidative/nitrative stress, and macrophage activation. γ-tocopherol has antioxidant and anti-inflammatory activity, but its disease relevance and molecular targets are unclear. Objectives: To test whether γ-tocopherol attenuates disease-associated inflammation and define the macrophage mechanism. Methods: Multi-omics integrated analysis combined with γ-tocopherol-treated COPD-like mouse models was performed to evaluate the anti-inflammatory effects of γ-tocopherol and identify its target cell populations. Furthermore, target prediction, cellular thermal shift assay, co-immunoprecipitation, and other experimental approaches were used to identify the molecular target of γ-tocopherol and elucidate the downstream mechanisms underlying its anti-inflammatory and antioxidant effects. Measurements and Main Results: COPD was associated with altered γ-tocopherol metabolism and vitamin E-related transcriptional programs. γ-tocopherol reduced inflammatory cell accumulation, nitric oxide metabolites, macrophage activation, and lung inflammation in COPD-like mouse models. Alveolar macrophages were identified as the primary target cell population of γ-tocopherol in lung tissue. γ-tocopherol treatment suppressed nitric oxide synthesis and inflammatory cytokine release in macrophages, and this effect depended on the engagement of γ-tocopherol with PSEN1. Further mechanistic analysis identified SYT7 as a downstream effector of PSEN1, linking γ-tocopherol treatment to reduced PI3K/AKT signaling activity and attenuated inflammatory readouts. Conclusions: γ-tocopherol attenuates macrophage-centered inflammation in COPD-like models through a PSEN1–SYT7–PI3K/AKT signaling axis.

ORGANISM(S): Mus musculus

PROVIDER: GSE336580 | GEO | 2026/06/26

REPOSITORIES: GEO

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Project description:Mutations in PSEN1 cause familial Alzheimer’s disease with almost complete penetrance. Age at onset is highly variable between different PSEN1 mutations and even within families with the same mutation. Current research into late onset Alzheimer’s disease implicates inflammation in both disease onset and progression. PSEN1 is the catalytic subunit of gamma-secretase, responsible for regulated intramembrane proteolysis of numerous substrates that include cytokine receptors. For this reason, we tested the hypothesis that mutations in PSEN1 impact inflammatory responses in astrocytes, thereby contributing to disease progression. We developed patient-derived models of iPSC-astrocytes, representing three lines harbouring PSEN1 mutations and six control lines (including two isogenic controls). Transcriptomic and biochemical assays were used to investigate differential inflammatory responses to TNFa, IL1a and C1q. We show that PSEN1 is upregulated in response to inflammatory stimuli, and this upregulation is disrupted by pathological PSEN1 mutations. Using transcriptomic analyses, we demonstrate that PSEN1 mutant astrocytes have an augmented inflammatory profile in their basal state, concomitant with gene expression signatures revealing dysregulated intramembrane proteolysis and JAK-STAT signalling. Detailed investigation of the JAK-STAT2 signalling pathway showed reduced cell surface expression of IFNAR2, lower STAT2 phosphorylation cascades and delayed NFκB nuclear localisation in PSEN1 mutant astrocytes in response to inflammatory stimuli, thereby implicating the notion of altered cytokine signalling cascades. Finally, we use small molecule modulators of gamma-secretase to confirm a role for PSEN1/gamma-secretase in regulating the astrocytic response to inflammatory stimuli. Together, these data suggest that mutations in PSEN1 enhance cytokine signalling via impaired regulated intramembrane proteolysis, thereby predisposing astrocytic inflammatory profiles. These findings support a two-hit contribution of PSEN1 mutations to fAD pathogenesis, not only impacting APP and Abeta processing but also altering the cellular response to inflammation.

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γ-Tocopherol attenuates COPD-associated macrophage inflammation through the PSEN1–SYT7–PI3K/Akt axis

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