Novel insights into neuroinflammation: bacterial lipopolysaccharide, tumor necrosis factor α, and Ureaplasma species differentially modulate atypical chemokine receptor 3 responses in human brain microvascular endothelial cells

Abstract

BackgroundAtypical chemokine receptor 3 (ACKR3, synonym CXCR7) is increasingly considered relevant in neuroinflammatory conditions, in which its upregulation contributes to compromised endothelial barrier function and may ultimately allow inflammatory brain injury. While an impact of ACKR3 has been recognized in several neurological autoimmune diseases, neuroinflammation may also result from infectious agents, including Ureaplasma species (spp.). Although commonly regarded as commensals of the adult urogenital tract, Ureaplasma spp. may cause invasive infections in immunocompromised adults as well as in neonates and appear to be relevant pathogens in neonatal meningitis. Nonetheless, clinical and in vitro data on Ureaplasma-induced inflammation are scarce.MethodsWe established a cell culture model of Ureaplasma meningitis, aiming to analyze ACKR3 variances as a possible pathomechanism in Ureaplasma-associated neuroinflammation. Non-immortalized human brain microvascular endothelial cells (HBMEC) were exposed to bacterial lipopolysaccharide (LPS) or tumor necrosis factor-α (TNF-α), and native as well as LPS-primed HBMEC were cultured with Ureaplasma urealyticum serovar 8 (Uu8) and U. parvum serovar 3 (Up3). ACKR3 responses were assessed via qRT-PCR, RNA sequencing, flow cytometry, and immunocytochemistry.ResultsLPS, TNF-α, and Ureaplasma spp. influenced ACKR3 expression in HBMEC. LPS and TNF-α significantly induced ACKR3 mRNA expression (p < 0.001, vs. control), whereas Ureaplasma spp. enhanced ACKR3 protein expression in HBMEC (p < 0.01, vs. broth control). Co-stimulation with LPS and either Ureaplasma isolate intensified ACKR3 responses (p < 0.05, vs. LPS). Furthermore, stimulation wielded a differential influence on the receptor’s ligands.ConclusionsWe introduce an in vitro model of Ureaplasma meningitis. We are able to demonstrate a pro-inflammatory capacity of Ureaplasma spp. in native and, even more so, in LPS-primed HBMEC, underlining their clinical relevance particularly in a setting of co-infection. Furthermore, our data may indicate a novel role for ACKR3, with an impact not limited to auto-inflammatory diseases, but extending to infection-related neuroinflammation as well. AKCR3-induced blood-brain barrier breakdown might constitute a potential common pathomechanism.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1170-0) contains supplementary material, which is available to authorized users.

Chronic Intra-Uterine Ureaplasma parvum Infection Induces Injury of the Enteric Nervous System in Ovine Fetuses

“…and, consequently, temporarily increased diapedesis, which could at least in part be responsible for the observed increase in CD3positive cells. The latter suggestion is supported by previous in vitro findings showing enhanced endothelial protein expression of the cell adhesion molecule CXCR7 following co-incubation with LPS and UP, which was not observed in independently UPor LPS-exposed cells (36).…”

A case of Ureaplasma parvum meningitis in an adult after transphenoidal ablation of craniopharyngioma

“…Extragenital infections are rare in adults, even if cases of sternal wound infections, mediastinitis, aortic graft infections, arthritis or renal abscesses have been reported, especially in immunocompromised patients (Waites and Bébéar, 2019). Recently, a study established a model of Ureaplasma meningitis using human brain microvascular endothelial cells originating from adult human brain cortex (Silwedel et al, 2018). A pro-inflammatory capacity of Ureaplasma was reported in these cells, enhancing the expression of atypical chemokine receptor 3 (AKCR3), suggesting a role in blood-brain barrier breakdown (Silwedel et al, 2018).…”

“…Recently, a study established a model of Ureaplasma meningitis using human brain microvascular endothelial cells originating from adult human brain cortex (Silwedel et al, 2018). A pro-inflammatory capacity of Ureaplasma was reported in these cells, enhancing the expression of atypical chemokine receptor 3 (AKCR3), suggesting a role in blood-brain barrier breakdown (Silwedel et al, 2018). This observation partly enlightened the pathophysiological mechanism of Ureaplasma meningitis.…”

More than just inflammation: Ureaplasma species induce apoptosis in human brain microvascular endothelial cells

“…Cultures were kept in a humid atmosphere at 37 °C with 5% CO 2 . Confluent monolayers were expanded as described previously [19], and experiments were coherently conducted with recently thawed cells at passage 8. Basic endothelial cell attributes of HBMEC (characteristic spindle-shaped growth pattern and expression of the endothelial marker CD31) as well as inducibility of intercellular adhesion molecule 1 had been confirmed in preliminary experiments [19].…”

“…are scarce [16–18]. We recently established a cell culture model of Ureaplasma meningitis [19], using human brain microvascular endothelial cells (HBMEC), important constituents of the blood-brain barrier (BBB) and among the first cells to encounter pathogens seeking entry into the central nervous system (CNS) [20]. Having detected Ureaplasma -induced responses of atypical chemokine receptor 3, which may ultimately mediate BBB breakdown, we were the first to provide in vitro evidence of Ureaplasma -driven neuroinflammation [19].…”