Reversible CD8 T cell–neuron cross-talk causes aging-dependent neuronal regenerative decline

Zhou, Luming; Kong, Guiping; Palmisano, Ilaria; Cencioni, Maria Teresa; Danzi, Matt C.; Virgiliis, Francesco De; Chadwick, Jessica S; Crawford, Greg; Yu, Zicheng; Winter, Fred de; Bixby, John L.; Puttagunta, Radhika; Verhaagen, Joost; Pospori, C; Celso, Cristina Lo; Strid, Jessica; Botto, Marina; Giovanni, Simone Di

doi:10.1126/science.abd5926

Cited by 33 publications

(21 citation statements)

References 46 publications

(51 reference statements)

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“…Chemokines have been reported to be actively involved in CNS development and neurological diseases [ 14 ]. Chemokine signaling affects a variety of cellular activities and functions, including the migration and survival of neuronal precursors [ 17 ], the migration and proliferation of oligodendrocyte progenitors [ 18 ], the maintenance of oligodendrocyte lineage, myelination, and white matter [ 19 ], the central synaptic transmission [ 20 ], glymphatic function and neuroinflammation [ 21 ], and aging-dependent neuronal regenerative decline [ 22 ].…”

Section: Introductionmentioning

confidence: 99%

Convergent transcriptomic and genomic evidence supporting a dysregulation of CXCL16 and CCL5 in Alzheimer’s disease

Zhang

et al. 2023

Alz Res Therapy

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Background Neuroinflammatory factors, especially chemokines, have been widely reported to be involved in the pathogenesis of Alzheimer’s disease (AD). It is unclear how chemokines are altered in AD, and whether dysregulation of chemokines is the cause, or the consequence, of the disease. Methods We initially screened the transcriptomic profiles of chemokines from publicly available datasets of brain tissues of AD patients and mouse models. Expression alteration of chemokines in the blood from AD patients was also measured to explore whether any chemokine might be used as a potential biomarker for AD. We further analyzed the association between the coding variants of chemokine genes and genetic susceptibility of AD by targeted sequencing of a Han Chinese case–control cohort. Mendelian randomization (MR) was performed to infer the causal association of chemokine dysregulation with AD development. Results Three chemokine genes (CCL5, CXCL1, and CXCL16) were consistently upregulated in brain tissues from AD patients and the mouse models and were positively correlated with Aβ and tau pathology in AD mice. Peripheral blood mRNA expression of CXCL16 was upregulated in mild cognitive impairment (MCI) and AD patients, indicating the potential of CXCL16 as a biomarker for AD development. None of the coding variants within any chemokine gene conferred a genetic risk to AD. MR analysis confirmed a causal role of CCL5 dysregulation in AD mediated by trans-regulatory variants. Conclusions In summary, we have provided transcriptomic and genomic evidence supporting an active role of dysregulated CXCL16 and CCL5 during AD development.

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Section: Introductionmentioning

confidence: 99%

Convergent transcriptomic and genomic evidence supporting a dysregulation of CXCL16 and CCL5 in Alzheimer’s disease

Zhang

et al. 2023

Alz Res Therapy

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“…However, this model does present limitations, given that non-neuronal cells are not present and thus contributions from satellite glial cells ( Avraham et al, 2020 , 2021 ), immune cells ( Niemi et al, 2013 ) or other extrinsic factors, such as the microbiome ( Serger et al, 2022 ), are not contributing to the neuronal response to injury. This model also does not allow to study the age-dependent neuronal regenerative decline ( Zhou et al, 2022 ). The strengths of this model lie in the ability to study intrinsic neuronal mechanisms that regulate axon growth capacity in a defined and characterized neuronal population that are accessible to genetic and pharmacological manipulations.…”

Section: Discussionmentioning

confidence: 99%

Analysis of neuronal injury transcriptional response identifies CTCF and YY1 as co-operating factors regulating axon regeneration

Avraham

Lê²,

Leahy³

et al. 2022

Front. Mol. Neurosci.

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Injured sensory neurons activate a transcriptional program necessary for robust axon regeneration and eventual target reinnervation. Understanding the transcriptional regulators that govern this axon regenerative response may guide therapeutic strategies to promote axon regeneration in the injured nervous system. Here, we used cultured dorsal root ganglia neurons to identify pro-regenerative transcription factors. Using RNA sequencing, we first characterized this neuronal culture and determined that embryonic day 13.5 DRG (eDRG) neurons cultured for 7 days are similar to e15.5 DRG neurons in vivo and that all neuronal subtypes are represented. This eDRG neuronal culture does not contain other non-neuronal cell types. Next, we performed RNA sequencing at different time points after in vitro axotomy. Analysis of differentially expressed genes revealed upregulation of known regeneration associated transcription factors, including Jun, Atf3 and Rest, paralleling the axon injury response in vivo. Analysis of transcription factor binding sites in differentially expressed genes revealed other known transcription factors promoting axon regeneration, such as Myc, Hif1α, Pparγ, Ascl1a, Srf, and Ctcf, as well as other transcription factors not yet characterized in axon regeneration. We next tested if overexpression of novel candidate transcription factors alone or in combination promotes axon regeneration in vitro. Our results demonstrate that expression of Ctcf with Yy1 or E2f2 enhances in vitro axon regeneration. Our analysis highlights that transcription factor interaction and chromatin architecture play important roles as a regulator of axon regeneration.

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“…This level increases upon sciatic nerve injury. Moreover, the level of RPS6 phosphorylation decreases in neurons during development and ageing, which again correlates with the decrease of regenerative ability [26, 29]. All these observations suggest a strong connection between the phosphorylation state of RPS6 and the regenerative outcome.…”

Section: Discussionmentioning

confidence: 99%

The RSK-RPS6 Axis Controls the Preconditioning Effect and Induces Spinal Cord Regeneration

Decourt

Schaeffer

Blot

et al. 2022

Preprint

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Unlike immature neurons and neurons from the peripheral nervous system (PNS), mature neurons from the central nervous system (CNS) cannot regenerate after injury. In the past 15 years, huge progress has been made to identify molecules and pathways necessary for neuroprotection and/or regeneration after CNS injury. In most regenerative models, phosphorylated ribosomal protein S6 (p-S6) is upregulated in neurons, which is often associated with an activation of the mTOR pathway. However, the exact contribution of post-translational modifications of this ribosomal protein in CNS regeneration remains elusive. In this study, we demonstrate that RPS6 phosphorylation is essential for PNS and CNS regeneration. We show that this phosphorylation is induced during the preconditioning effect in dorsal root ganglion (DRG) neurons, and that it is controlled by the p90S6 kinase RSK2. Our results reveal that RSK2 controls the preconditioning effect and that the RSK2-RPS6 axis is key for this process, as well as for PNS regeneration. Finally, we demonstrate that RSK2 promotes CNS regeneration in the dorsal column and allows functional recovery. Our data establish the critical role of RPS6 phosphorylation controlled by RSK2 in CNS regeneration and give new insights into the mechanism related to axon growth and circuit formation after traumatic lesion.

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Reversible CD8 T cell–neuron cross-talk causes aging-dependent neuronal regenerative decline

Cited by 33 publications

References 46 publications

Convergent transcriptomic and genomic evidence supporting a dysregulation of CXCL16 and CCL5 in Alzheimer’s disease

Convergent transcriptomic and genomic evidence supporting a dysregulation of CXCL16 and CCL5 in Alzheimer’s disease

Analysis of neuronal injury transcriptional response identifies CTCF and YY1 as co-operating factors regulating axon regeneration

The RSK-RPS6 Axis Controls the Preconditioning Effect and Induces Spinal Cord Regeneration

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