Neuronal and BBB damage induced by sera from patients with secondary progressive multiple sclerosis

Proia, Patrizia; Schiera, Gabriella; Salemi, Giuseppe; Ragonese, Paolo; Savettieri, Giovanni; Liegro, Italia Di

doi:10.3892/ijmm_00000287

Cited by 5 publications

(1 citation statement)

References 31 publications

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“…It has been reported that BBB disruption could be caused by gut microbiota dysbiosis, leading to the pathogenic antigen and serum protein leakage into CNS. This process has been previously demonstrated in the studies of schizophrenia, depression, Alzheimer’s disease (AD), Parkinson’s disease (PD) and MS, although the exact route is unclear [ 39 , 47 , 49 – 52 ].…”

Section: Discussionmentioning

confidence: 95%

Constipation induced gut microbiota dysbiosis exacerbates experimental autoimmune encephalomyelitis in C57BL/6 mice

Lin

Liu

et al. 2021

J Transl Med

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Background Constipation is a common gastrointestinal dysfunction which has a potential impact on people's immune state and their quality of life. Here we investigated the effects of constipation on experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Methods Constipation was induced by loperamide in female C57BL/6 mice. The alternations of gut microbiota, permeability of intestinal barrier and blood–brain barrier, and histopathology of colon were assessed after constipation induction. EAE was induced in the constipation mice. Fecal microbiota transplantation (FMT) was performed from constipation mice into microbiota-depleted mice. Clinical scores, histopathology of inflammation and demyelination, Treg/Th17 and Treg17/Teff17 imbalance both in the peripheral lymphatic organs and central nervous system, cytokines include TGF-β, GM-CSF, IL-10, IL-17A, IL-17F, IL-21, IL-22, and IL-23 in serum were assessed in different groups. Results Compared with the vehicle group, the constipation mice showed gut microbiota dysbiosis, colon inflammation and injury, and increased permeability of intestinal barrier and blood–brain barrier. We found that the clinical and pathological scores of the constipation EAE mice were severer than that of the EAE mice. Compared with the EAE mice, the constipation EAE mice showed reduced percentage of Treg and Treg17 cells, increased percentage of Th17 and Teff17 cells, and decreased ratio of Treg/Th17 and Treg17/Teff17 in the spleen, inguinal lymph nodes, brain, and spinal cord. Moreover, the serum levels of TGF-β, IL-10, and IL-21 were decreased while the GM-CSF, IL-17A, IL-17F, IL-22, and IL-23 were increased in the constipation EAE mice. In addition, these pathological processes could be transferred via their gut microbiota. Conclusions Our results verified that constipation induced gut microbiota dysbiosis exacerbated EAE via aggravating Treg/Th17 and Treg17/Teff17 imbalance and cytokines disturbance in C57BL/6 mice.

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Section: Discussionmentioning

confidence: 95%

Constipation induced gut microbiota dysbiosis exacerbates experimental autoimmune encephalomyelitis in C57BL/6 mice

Lin

Liu

et al. 2021

J Transl Med

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Transition from identity to bioactivity‐guided proteomics for biomarker discovery with focus on the PF2D platform

Ménoret

Crocker

Rodríguez

et al. 2015

Proteomics Clinical Apps

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Proteomic strategies provide a valuable tool kit to identify proteins involved in diseases. With recent progress in MS technology, high throughput proteomics has accelerated protein identification for potential biomarkers. Numerous biomarker candidates have been identified in several diseases, and many are common among pathologies. An overall strategy that could complement and strengthen the search for biomarkers is combining protein identity with biological outcomes. This review describes an emerging framework of bridging bioactivity to protein identity, exploring the possibility that some biomarkers will have a mechanistic role in the disease process. A review of pulmonary, cardiovascular, and CNS biomarkers will be discussed to demonstrate the utility of combining bioactivity with identification as a means to not only find meaningful biomarkers, but also to uncover functional mediators of disease.

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Identification of an essential endogenous regulator of blood–brain barrier integrity, and its pathological and therapeutic implications

Cristante

McArthur

Mauro

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

173

218

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The blood-brain barrier (BBB), a critical guardian of communication between the periphery and the brain, is frequently compromised in neurological diseases such as multiple sclerosis (MS), resulting in the inappropriate passage of molecules and leukocytes into the brain. Here we show that the glucocorticoid anti-inflammatory messenger annexin A1 (ANXA1) is expressed in brain microvascular endothelial cells, where it regulates BBB integrity. In particular, ANXA1 −/− mice exhibit significantly increased BBB permeability as a result of disrupted interendothelial cell tight junctions, essentially related to changes in the actin cytoskeleton, which stabilizes tight and adherens junctions. This situation is reminiscent of early MS pathology, a relationship confirmed by our detection of a selective loss of ANXA1 in the plasma and cerebrovascular endothelium of patients with MS. Importantly, this loss is swiftly restored by i.v. administration of human recombinant ANXA1. Analysis in vitro confirms that treatment of cerebrovascular endothelial cells with recombinant ANXA1 restores cell polarity, cytoskeleton integrity, and paracellular permeability through inhibition of the small G protein RhoA. We thus propose ANXA1 as a critical physiological regulator of BBB integrity and suggest it may have utility in the treatment of MS, correcting BBB function and hence ameliorating disease.T he presence of narrow and dense tight junctions between adjacent endothelial cells is peculiar to the cerebral vasculature, and their integrity is essential for the maintenance of correct blood-brain barrier (BBB) function as the primary regulator of cross-talk between the brain and the rest of the body (1). Increasing evidence indicates that the integrity of this structural and functional barrier is compromised in neurological conditions such as multiple sclerosis (MS), Alzheimer's, and Parkinson diseases, leading to the failure of the normal mechanisms controlling passage of substances into the brain (2) and to the sensitization and/or worsening of pathologic conditions. Pharmacological intervention to prevent or correct BBB alteration in such diseases is a difficult task, but potential therapeutic leads can be gained from the study of endogenous mediators regulating barrier integrity.Annexin A1 (ANXA1) is an important anti-inflammatory protein, principally known as a regulator of peripheral leukocyte migration and a promoter of macrophage phagocytosis (3). ANXA1 is expressed in several cell types within the brain, including ependyma and microglia, but in particular in the endothelium of the brain microvasculature (4), although its role in these cells remains obscure. We have previously shown glucocorticoids to up-regulate expression of ANXA1 in the cerebral endothelium (5), and, given that glucocorticoids enhance BBB tightness (6), we hypothesized that ANXA1 may play a role in the regulation of BBB permeability. Through combined in vitro and in vivo approaches, we have identified a dual role for ANXA1 in organizing the interendothelial cell...

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Neuronal and BBB damage induced by sera from patients with secondary progressive multiple sclerosis

Cited by 5 publications

References 31 publications

Constipation induced gut microbiota dysbiosis exacerbates experimental autoimmune encephalomyelitis in C57BL/6 mice

Constipation induced gut microbiota dysbiosis exacerbates experimental autoimmune encephalomyelitis in C57BL/6 mice

Transition from identity to bioactivity‐guided proteomics for biomarker discovery with focus on the PF2D platform

Identification of an essential endogenous regulator of blood–brain barrier integrity, and its pathological and therapeutic implications

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