IP-10 Promotes Blood–Brain Barrier Damage by Inducing Tumor Necrosis Factor Alpha Production in Japanese Encephalitis

Abstract

Japanese encephalitis is a neuropathological disorder caused by Japanese encephalitis virus (JEV), which is characterized by severe pathological neuroinflammation and damage to the blood–brain barrier (BBB). Inflammatory cytokines/chemokines can regulate the expression of tight junction (TJ) proteins and are believed to be a leading cause of BBB disruption, but the specific mechanisms remain unclear. IP-10 is the most abundant chemokine produced in the early stage of JEV infection, but its role in BBB disruption is unknown. The administration of IP-10-neutralizing antibody ameliorated the decrease in TJ proteins and restored BBB integrity in JEV-infected mice. In vitro study showed IP-10 and JEV treatment did not directly alter the permeability of the monolayers of endothelial cells. However, IP-10 treatment promoted tumor necrosis factor alpha (TNF-α) production and IP-10-neutralizing antibody significantly reduced the production of TNF-α. Thus, TNF-α could be a downstream cytokine of IP-10, which decreased TJ proteins and damaged BBB integrity. Further study indicated that JEV infection can stimulate upregulation of the IP-10 receptor CXCR3 on astrocytes, resulting in TNF-α production through the JNK-c-Jun signaling pathway. Consequently, TNF-α affected the expression and cellular distribution of TJs in brain microvascular endothelial cells and led to BBB damage during JEV infection. Regarding regulation of the BBB, the IP-10/TNF-α cytokine axis could be considered a potential target for the development of novel therapeutics in BBB-related neurological diseases.

Zika Virus Infection Promotes Local Inflammation, Cell Adhesion Molecule Upregulation, and Leukocyte Recruitment at the Blood-Brain Barrier

“…In this study, we found that the chemoattractive molecules CXCL10, CCL5, and CCL2 were potently released by the apical compartment upon ZIKV hBLEC infection, suggesting that circulating leukocytes could be attracted to the infected BBB. CXCL10 is emerging as a key inflammatory molecule expressed during neuroinflammatory processes such as autoimmune disorders (e.g., multiple sclerosis [55] or encephalitis [47,56]). It is involved in the recruitment of T cells to the BBB and was proposed to favor inflammatory cell recruitment into the CNS following rabies virus infection (56).…”

“…Recent studies and our results suggest that ZIKV can directly infect BBB cells but may not have a strong deleterious effect on BBB integrity and that viral particles could be released basolaterally and reach the CNS ( 21 ). Other arboviruses such as WNV and JEV lead to endothelium integrity impairment and inflammatory molecule production that will disrupt BBB integrity and further allow virus CNS access ( 19 , 47 ). Among these cytokines, tumor necrosis factor alpha (TNF-α), IL-1β, transforming growth factor beta (TGF-β), and IL-6 have been shown to modulate BBB permeability by several mechanisms, including downregulation or relocalization of junction proteins such as occludin and ZO-1 ( 48 , 49 ).…”

Brain Microvascular Endothelial Cells-Derived HMGB1 Facilitates Monocyte Transendothelial Migration Favoring JEV Neuroinvasion

“…Our previous results revealed that JEV itself caused no signi cant damage to the tight junctions of endothelial cells during early infection, which was different to other neurotropic Flaviviridae such as WNV [6,61,62]. On the contrary, the JEV-infected brain supernatant containing MMPs, IL-6, TNF-, CCL-2 and other soluble pro-in ammatory factors, dramatically destroyed the integrity of endothelial cells monolayer in vitro, supporting that the systemic in ammatory response breakdown the BBB during early infection [8,11,63].…”

Comparative analysis of neuroinvasion by Japanese encephalitis virulent and vaccine strains in anin cellulomodel of human blood-brain barrier

“…While in vivo approaches are useful to understand the systemic viral disease, in vitro models are also useful because they allow studying the molecular mechanisms that govern viral pathogenesis. In this regard, previous approaches have been used to characterize JEV neuroinvasion properties at late times of infection, mainly 24 hpi or later [30, 33–35]. However, knowledge relative to the early times of JEV contact with the BBB is poor, if not null.…”