IFN-γ, IL-17A, or zonulin rapidly increase the permeability of the blood-brain and small intestinal epithelial barriers: Relevance for neuro-inflammatory diseases

Rahman, Mohammed Tanjimur; Ghosh, Chaitali; Hossain, Mohammed; Linfield, Debra T.; Rezaee, Fariba; Janigro, Damir; Marchi, Nicola; Boxel-Dezaire, Anette H.H. van

doi:10.1016/j.bbrc.2018.11.021

Cited by 126 publications

(90 citation statements)

References 38 publications

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“…The presence of IL-6 signaling alongside IL-17A was shown to be important on disrupting barrier function in hCMEC/D3 human brain endothelial cell line, by decreasing the expression of genes encoding tight junction, adherens junction and adhesion proteins. IL-17A has also been reported to disrupt the BBB through modification of the localization of TJ proteins and the underlying cytoskeleton (Rahman et al, 2018). Therefore, multiple levels of regulation of this process by IL-17A are possible.…”

Section: Discussionmentioning

confidence: 99%

“…IL-17A and IL-17F form homo-or heterodimers that bind to the IL-17 receptor complex (IL-17RA and IL-17RC) (Waisman et al, 2015). IL-17 disrupts barrier integrity of both human brain-derived primary microvascular endothelial cells (Kebir et al, 2007;Rahman et al, 2018) and a murine brain endothelial cell line, bEnd.3 (Huppert et al, 2010). IL-17 is important for the development of experimental autoimmune encephalomyelitis (EAE) (Langrish et al, 2005;McGinley et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

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IL-17A is associated with the breakdown of the blood-brain barrier in relapsing-remitting multiple sclerosis

Setiadi¹,

Abbas²,

Jeet³

et al. 2019

Journal of Neuroimmunology

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A B S T R A C TIL-17 has been implicated in the pathogenesis of multiple sclerosis (MS). Here, we show that blockade of IL-17A, but not IL-17F, attenuated experimental autoimmune encephalomyelitis (EAE). We further show that IL-17A levels were elevated in the CSF of relapsing-remitting MS (RRMS) patients and that they correlated with the CSF/ serum albumin quotient (Qalb), a measure of blood-brain barrier (BBB) dysfunction. We then demonstrated that the combination of IL-17A and IL-6 reduced the expression of tight junction (TJ)-associated genes and disrupted monolayer integrity in the BBB cell line hCMEC/D3. However, unlike IL-17A, IL-6 in the CSF from RRMS patients did not correlate with Qalb. These data highlight the potential importance of targeting IL-17A in preserving BBB integrity in RRMS.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

IL-17A is associated with the breakdown of the blood-brain barrier in relapsing-remitting multiple sclerosis

Setiadi¹,

Abbas²,

Jeet³

et al. 2019

Journal of Neuroimmunology

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“…Our data suggest that serum zonulin levels in males may represent a different pattern of gut integrity compared to females. A recently published study showed that zonulin has the potential to enhance the permeability of both the GBB and the BBB [30]. Zonulin causes a dysregulation of the endothelial tight junctions of these barriers [10].…”

Section: Disease Markersmentioning

confidence: 99%

Sex-Specific Associations of Trimethylamine-N-Oxide and Zonulin with Signs of Depression in Carbohydrate Malabsorbers and Nonmalabsorbers

et al. 2020

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Background. The microbiome-derived trimethylamine-N-oxide (TMAO) and the intestinal permeability marker zonulin are considered to be linked with depression. Moreover, carbohydrate malabsorption (CMA) was shown to be associated with signs of depression. This study is aimed at investigating possible sex-specific associations between TMAO and zonulin and the presence of depressive signs in individuals with and without CMA. Methods. Serum concentrations of TMAO and zonulin were determined in 115 and 136 individuals with the presence or absence of CMA. All 251 study participants underwent lactase gene C/T-13910 polymorphism genotyping and fructose H2/CH4 breath testing. Additionally, they filled in the Beck Depression Inventory (BDI-II) questionnaire. Results. The median TMAO and zonulin serum concentrations were 2.66 (1.93–4.14) μmol/L and 40.83 (34.73–47.48) ng/mL. Serum TMAO levels were positively correlated with depressive symptoms (P=0.011, ρ=0.160). The strongest correlations were observed in 87 females (P=0.010, ρ=0.274) and 49 males (P=0.027, ρ=0.315) without CMA, whereas 115 patients with CMA showed no significant correlations. Zonulin tended to be negatively correlated with the BDI-II score in 49 males without CMA (P=0.062, ρ=−0.269). Conclusion. This study demonstrates a positive correlationship between the serum TMAO concentrations and the severity of depressive symptoms in females and males without CMA. Serum zonulin levels were negatively correlated with signs of depression in males without CMA. These findings suggest a gender-specific relationship between the serum TMAO and zonulin concentrations, depression, and CMA.

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“…These examples highlight the need of tightly regulated intestinal and brain barriers (Rahman et al, 2018). In AD, a dysbiotic GM may enhance gut permeability and alter BBB integrity, allowing the access of infectious agents or associated molecules into the brain (Martin et al, 2018).…”

Section: The Gut-brain Axis and Neurodegeneration: Is There A Barriermentioning

confidence: 99%

“…Significantly, intestinal and brain barriers are reactive to analogous proinflammatory triggers. Circulating inflammatory cytokines IL-17, interferon-gamma (IFN-γ), and the small intestine epithelium protein zonulin can damage the intestinal-epithelia and BBBs (Rahman et al, 2018).…”

Section: The Gut-brain Axis and Neurodegeneration: Is There A Barriermentioning

confidence: 99%

Peripheral Routes to Neurodegeneration: Passing Through the Blood–Brain Barrier

Giannoni

Claeysen

Noè

et al. 2020

Front. Aging Neurosci.

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A bidirectional crosstalk between peripheral players of immunity and the central nervous system (CNS) exists. Hence, blood-brain barrier (BBB) breakdown is emerging as a participant mechanism of dysregulated peripheral-CNS interplay, promoting diseases. Here, we examine the implication of BBB damage in neurodegeneration, linking it to peripheral brain-directed autoantibodies and gut-brain axis mechanisms. As BBB breakdown is a factor contributing to, or even anticipating, neuronal dysfunction(s), we here identify contemporary pharmacological strategies that could be exploited to repair the BBB in disease conditions. Developing neurovascular, add on, therapeutic strategies may lead to a more efficacious pre-clinical to clinical transition with the goal of curbing the progression of neurodegeneration.

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IFN-γ, IL-17A, or zonulin rapidly increase the permeability of the blood-brain and small intestinal epithelial barriers: Relevance for neuro-inflammatory diseases

Cited by 126 publications

References 38 publications

IL-17A is associated with the breakdown of the blood-brain barrier in relapsing-remitting multiple sclerosis

IL-17A is associated with the breakdown of the blood-brain barrier in relapsing-remitting multiple sclerosis

Sex-Specific Associations of Trimethylamine-N-Oxide and Zonulin with Signs of Depression in Carbohydrate Malabsorbers and Nonmalabsorbers

Peripheral Routes to Neurodegeneration: Passing Through the Blood–Brain Barrier

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