A TLR/CD44 axis regulates T cell trafficking in experimental and human multiple sclerosis

Tredicine, Maria; Camponeschi, Chiara; Pirolli, Davide; Lucchini, Matteo; Valentini, Mariagrazia; Geloso, Maria Concetta; Mirabella, Massimiliano; Fidaleo, Marco; Righino, Benedetta; Moliterni, Camilla; Giorda, Ezio; Rende, Mario; Rosa, Maria Cristina De; Foti, Maria; Constantin, Gabriela; Ria, Francesco; Sante, Gabriele Di

doi:10.1016/j.isci.2022.103763

Cited by 15 publications

(13 citation statements)

References 60 publications

(90 reference statements)

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“…Experimental autoimmune encephalomyelitis was induced in female SJL/J mice (6–8 weeks old; Charles River Laboratories, Calco, Italy) as described ( Marchese et al, 2021 ; Tredicine et al, 2022 ). Briefly, mice were subcutaneously injected, on day post immunization (d.p.i.)…”

Section: Methodsmentioning

confidence: 99%

Regionally restricted modulation of Sam68 expression and Arhgef9 alternative splicing in the hippocampus of a murine model of multiple sclerosis

Adinolfi

Sante²,

Vaccari³

et al. 2023

Front. Mol. Neurosci.

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Multiple sclerosis (MS) and its preclinical models are characterized by marked changes in neuroplasticity, including excitatory/inhibitory imbalance and synaptic dysfunction that are believed to underlie the progressive cognitive impairment (CI), which represents a significant clinical hallmark of the disease. In this study, we investigated several parameters of neuroplasticity in the hippocampus of the experimental autoimmune encephalomyelitis (EAE) SJL/J mouse model, characterized by rostral inflammatory and demyelinating lesions similar to Relapsing–Remitting MS. By combining morphological and molecular analyses, we found that the hippocampus undergoes extensive inflammation in EAE-mice, more pronounced in the CA3 and dentate gyrus (DG) subfields than in the CA1, associated with changes in GABAergic circuitry, as indicated by the increased expression of the interneuron marker Parvalbumin selectively in CA3. By laser-microdissection, we investigated the impact of EAE on the alternative splicing of Arhgef9, a gene encoding a post-synaptic protein playing an essential role in GABAergic synapses and whose mutations have been related to CI and epilepsy. Our results indicate that EAE induces a specific increase in inclusion of the alternative exon 11a only in the CA3 and DG subfields, in line with the higher local levels of inflammation. Consistently, we found a region-specific downregulation of Sam68, a splicing-factor that represses this splicing event. Collectively, our findings confirm a regionalized distribution of inflammation in the hippocampus of EAE-mice. Moreover, since neuronal circuit rearrangement and dynamic remodeling of structural components of the synapse are key processes that contribute to neuroplasticity, our study suggests potential new molecular players involved in EAE-induced hippocampal dysfunction.

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Section: Methodsmentioning

confidence: 99%

Regionally restricted modulation of Sam68 expression and Arhgef9 alternative splicing in the hippocampus of a murine model of multiple sclerosis

Adinolfi

Sante²,

Vaccari³

et al. 2023

Front. Mol. Neurosci.

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“…Thus, peripherally activated T cells speci c for myelin antigens become able to cross the blood-brain barrier. After reaching CNS, they recognize speci c targets able to re-stimulate them through local antigen-presenting cells (APCs) [34], causing damage to myelin sheaths and recruitment of other immune cells [35,36], leading to demyelination. The T cell-mediated selfreactivity against myelin is strongly linked to the human leucocyte antigen HLA-DRB1*15 allele (HLA-DR2).…”

Section: Discussionmentioning

confidence: 99%

Different HLA genotype pattern in patients with Multiple Sclerosis onset after COVID-19 vaccine.

Bianco,

Sante,

Colò

et al. 2023

Preprint

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Background: Few cases of Multiple Sclerosis (MS) onset after COVID-19 vaccination have been reported, even though the evidence is insufficient to establish causality. The aim of this study is to compare cases of newly diagnosed MS before and after the outbreak of COVID-19 pandemic and the impact of COVID-19 vaccination. Potential environmental and genetic predisposing factors were also investigated, as well as clinical patterns. Methods: This is a single-centre retrospective cohort study including all patients who presented with MS onset between January 2018 and July 2022. Data on COVID-19 vaccination administration, dose, and type were collected. HLA-DRB1 genotyping was performed in three subgroups. Results: 266 patients received a new diagnosis of MS in our centre, 143 before the COVID-19 pandemic (until and including March 2020) and 123 during COVID-19 era (from April 2020). The mean number of new MS onset per year was not different before and during COVID-19 era, as well as baseline patients’ characteristics, type of onset, clinical recovery, and radiological patterns. Fourteen (11.4%) patients who subsequently received a new diagnosis of MS had a history of COVID-19 vaccination within one month before symptoms onset. Patients’ characteristics, type of onset, clinical recovery, and radiological patterns do not differ from those of patients with non-vaccine-related new diagnosis of MS. The allele frequencies of HLA-DRB1*15 were 17.6% and 22.2% in patients with not-vaccine-related disease onset before and during COVID-19 era respectively, while no case of HLA-DRB1*15 was identified among patients with a new diagnosis of MS post-COVID-19 vaccine. In contrast HLA-DRB1*08+ or HLA-DRB1*10+ MS patients were present only in this subgroup. Conclusions: Although a causal link between COVID-19 vaccination and MS cannot be detected, it is interesting to note and speculate about the peculiarities and heterogeneities underlying disease mechanisms of MS, where the interactions of genetic and environment could be crucial also for the follow up and the evaluation of therapeutic options.

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“…qPCR was conducted on a StepOne System (Applied Biosystems, Thermo Fisher Scientific, Inc., Waltham, MA, USA) using a PowerUp SYBR Green Real-time PCR Master Mix (A25742 Applied Biosystems, Thermo Fisher Scientific, Inc., Waltham, MA, USA). The primers are shown in Supplementary Table S1 and, for the relative quantification of gene expression, were normalized to GAPDH and actine housekeeping genes [ 29 , 30 ].…”

Section: Methodsmentioning

confidence: 99%

Short-Term Effects of Side-Stream Smoke on Nerve Growth Factor and Its Receptors TrKA and p75NTR in a Group of Non-Smokers

Stabile

Pistilli

Bartolini

et al. 2022

IJERPH

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Environmental tobacco smoke remains a major risk factor, for both smokers and non-smokers, able to trigger the initiation and/or the progression of several human diseases. Although in recent times governments have acted with the aim of banning or strongly reducing its impact within public places and common spaces, environmental tobacco smoke remains a major pollutant in private places, such as the home environment or cars. Several inflammatory and long-term biomarkers have been analysed and well-described, but the list of mediators modulated during the early phases of inhalation of environmental tobacco smoke needs to be expanded. The aim of this study was to measure the short-term effects after exposure to side-stream smoke on Nerve Growth Factor and its receptors Tropomyosin-related kinase A and neurotrophin p75, molecules already described in health conditions and respiratory diseases. Twenty-one non-smokers were exposed to a home-standardized level of SS as well as to control smoke-free air. Nerve Growth Factor and inflammatory cytokines levels, as well the expression of Tropomyosin-related kinase A and neurotrophin receptor p75, were analysed in white blood cells. The present study demonstrates that during early phases, side-stream smoke exposure induced increases in the percentage of neurotrophin receptor p75-positive white blood cells, in their mean fluorescent intensity, and in gene expression. In addition, we found a positive correlation between the urine cotinine level and the percentage of neurotrophin receptor-positive white blood cells. For the first time, the evidence that short-term exposure to side-stream smoke is able to increase neurotrophin receptor p75 expression confirms the very early involvement of this receptor, not only among active smokers but also among non-smokers exposed to SS. Furthermore, the correlation between cotinine levels in urine and the increase in neurotrophin receptor p75-positive white blood cells could represent a potential novel molecule to be investigated for the detection of SS exposure at early time points.

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A TLR/CD44 axis regulates T cell trafficking in experimental and human multiple sclerosis

Cited by 15 publications

References 60 publications

Regionally restricted modulation of Sam68 expression and Arhgef9 alternative splicing in the hippocampus of a murine model of multiple sclerosis

Regionally restricted modulation of Sam68 expression and Arhgef9 alternative splicing in the hippocampus of a murine model of multiple sclerosis

Different HLA genotype pattern in patients with Multiple Sclerosis onset after COVID-19 vaccine.

Short-Term Effects of Side-Stream Smoke on Nerve Growth Factor and Its Receptors TrKA and p75NTR in a Group of Non-Smokers

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