Astrocytic expression of the CXCL12 receptor, CXCR7/ACKR3 is a hallmark of the diseased, but not developing CNS

Puchert, Malte; Pelkner, F.; Stein, Gregor; Angelov, Doychin N.; Boltze, Johannes; Wagner, Daniel-Christoph; Odoardi, Francesca; Flügel, Alexander; Streit, Wolfgang J.; Engele, Jürgen

doi:10.1016/j.mcn.2017.09.001

Cited by 21 publications

(23 citation statements)

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“…In animal models, ACKR3 was shown to be expressed within various brain regions, with an upregulation observable in case of inflammation, as for instance in EAE [ 29 ]. ACKR3 increases were furthermore found upon cytokine stimulation or induction of hypoxia in human astrocytes [ 30 ]. To date, only a single study addressed ACKR3 expression and inducibility in human brain endothelial cells [ 26 ].…”

Section: Introductionmentioning

confidence: 99%

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

Silwedel¹,

Speer²,

Haarmann

et al. 2018

J Neuroinflammation

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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.

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Section: Introductionmentioning

confidence: 99%

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

Silwedel¹,

Speer²,

Haarmann

et al. 2018

J Neuroinflammation

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Section: The Role Of Cxcr7 In Neurological Conditionsmentioning

confidence: 99%

“…CXCR4 and/or CXCR7, with their ligand CXCL12, are associated with many neurological and inflammatory conditions, as well as many cancers. CXCR7 is up-regulated in disease states including post-ischemic stroke [29,30], multiple sclerosis [31], Alzheimer's disease [32], epilepsy [33], rheumatoid arthritis [34], autism [35], and coronary artery disease [36]. Increased expression is also observed in many cancers, including prostate [16], pancreatic [37], ovarian [38], colon [39], kidney [40], liver [40], lung and breast [41] and CXCR7 is involved in the growth, metastasis and survival of these tumor cell lines.…”

Section: The Physiological Roles Of Cxcr7mentioning

confidence: 99%

“…In multiple sclerosis, the loss of CXCL12 occurs from abluminal surfaces in the CNS, while CXCR7 expression increases as a scavenger of CXCR12 [31]. In experimental autoimmune encephalomyelitis (EAE) models in rats, an animal model of MS, an increase in astrocytic CXCR7 expression in the spinal cord was observed [32]. This overexpression causes the chemotaxis of microglia and is correlated with disease severity [44].…”

Section: The Role Of Cxcr7 In Neurological Conditionsmentioning

confidence: 99%

“…An anti-CXCR7 antibody ameliorated the symptoms of EAE. Higher expression of CXCR7 is also detectable in the hippocampus of patients with Alzheimer's disease as well as after spinal cord compression [32]. In a mouse model of epilepsy, as well as in tissues of temporal lobe epilepsy patients, CXCR7 is up-regulated in the hippocampal dentate gyrus region [33].…”

Section: The Role Of Cxcr7 In Neurological Conditionsmentioning

confidence: 99%

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Advances in CXCR7 Modulators

Lounsbury

2020

Pharmaceuticals

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CXC chemokine receptor 7 (CXCR7) is a G-protein-coupled receptor that signals through the β-arrestin pathway. Its ligands include interferon-inducible T cell α chemoattractant (CXCL11) and stromal cell-derived factor-1 (CXCL12). It interacts with CXCR4, and the two are associated with various cancers, as well as other disease states such as coronary artery disease, stroke, inflammation and human immunodeficiency virus (HIV). Antibodies and small interfering RNA (siRNA) have shown the utility of antagonists of CXCR7 in these disease states. Although some small molecules were initially reported as antagonists due to their displayed activity, many function as agonists while still producing the desired pharmacologic effects. A potential reason for this contradiction is that effects may be due to elevated extracellular CXCL12 levels.

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ACKR3 Antagonism Enhances the Repair of Demyelinated Lesions Through Both Immunomodulatory and Remyelinating Effects

Pouzol,

Sassi,

Tunis

et al. 2024

Neurochem Res

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Addressing inflammation, demyelination, and associated neurodegeneration in inflammatory demyelinating diseases like multiple sclerosis (MS) remains challenging. ACT-1004-1239, a first-in-class and potent ACKR3 antagonist, currently undergoing clinical development, showed promise in preclinical MS models, reducing neuroinflammation and demyelination. However, its effectiveness in treating established disease and impact on remyelination after the occurrence of demyelinated lesions remain unexplored. This study assessed the therapeutic effect of ACT-1004-1239 in two demyelinating disease models. In the proteolipid protein (PLP)-induced experimental autoimmune encephalomyelitis (EAE) model, ACT-1004-1239 administered upon the detection of the first signs of paralysis, resulted in a dose-dependent reduction in EAE disease severity, concomitant with diminished immune cell infiltrates in the CNS and reduced demyelination. Notably, efficacy correlated with elevated plasma concentrations of CXCL11 and CXCL12, two pharmacodynamic biomarkers of ACKR3 antagonism. Combining ACT-1004-1239 with siponimod, an approved immunomodulatory treatment for MS, synergistically reduced EAE severity. In the cuprizone-induced demyelination model, ACT-1004-1239 administered after 5 weeks of cuprizone exposure, significantly accelerated remyelination, already quantifiable one week after cuprizone withdrawal. Additionally, ACT-1004-1239 penetrated the CNS, elevating brain CXCL12 concentrations. These results demonstrate that ACKR3 antagonism significantly reduces the severity of experimental demyelinating diseases, even when treatment is initiated therapeutically, after the occurrence of lesions. It confirms the dual mode of action of ACT-1004-1239, exhibiting both immunomodulatory effects by reducing neuroinflammation and promyelinating effects by accelerating myelin repair. The results further strengthen the rationale for evaluating ACT-1004-1239 in clinical trials for patients with demyelinating diseases.

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Astrocytic expression of the CXCL12 receptor, CXCR7/ACKR3 is a hallmark of the diseased, but not developing CNS

Cited by 21 publications

References 76 publications

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

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

Advances in CXCR7 Modulators

ACKR3 Antagonism Enhances the Repair of Demyelinated Lesions Through Both Immunomodulatory and Remyelinating Effects

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