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Atypical chemokine receptors in multiple sclerosis - towards a molecular understanding of chemokine gradients in inflammation

English title Atypical chemokine receptors in multiple sclerosis - towards a molecular understanding of chemokine gradients in inflammation
Applicant Mehling Matthias
Number 192751
Funding scheme Project funding (Div. I-III)
Research institution Departement Biomedizin Universität Basel
Institution of higher education University of Basel - BS
Main discipline Physiology : other topics
Start/End 01.04.2021 - 31.03.2025
Approved amount 632'000.00
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All Disciplines (2)

Discipline
Physiology : other topics
Cellular Biology, Cytology

Keywords (3)

chemokine gradient formation; multiple sclerosis; atypical chemokine receptors

Lay Summary (German)

Lead
Atypische Chemokin-Rezeptoren in der Multiplen Sklerose
Lay summary
Das Einwandern von Immunzellen spielt eine zentrale Rolle bei der Entstehung von Entzündungsherden in Gehirn und Rückenmark bei der Multiplen Sklerose. Die einwandernden Immunzellen werden in den Entzündungsherden der Multiplen Sklerose aktiviert und schütten Botenstoffen, sogenannten Zytokine, aus. Zytokine können in Astrozyten, den Stützzellen des Gehirns und des Rückenmarks, die Expression des zur Gruppe der Chemokine gehörenden Botenstoff CXCL12 induzieren. Gleichzeitig induzieren Zytokine auf Astozyten auch die Expression des atypischen Chemokinrezeptors ACKR3, der CXCL12 abfängt. Es ist bekannt, dass atypische Chemokinrezeptoren die Verteilung von Chemokinen beeinflussen und dadurch die Wanderung von Immunzellen steuern. 
Die Expression von ACKR3 auf Astrozyten legt nahe, dass dadurch die Verteilung von CxCL12 in Entzündungsherden des Gehirns und des Rückenmarks reguliert wird. Unklar ist, wie die Expression von ACKR3 und CXCL12 während der Entstehung von Entzündungsherden zeitlich und molekular reguliert wird. Ziel unseres Forschungsprojektes ist es, die molekularen Mechanismen der Expression von ACKR3 und CXCL12 und den zeitlichen Verlauf der Expression während der Entstehung von Entzündungsherden zu verstehen. 
Direct link to Lay Summary Last update: 07.02.2021

Responsible applicant and co-applicants

Abstract

Extensive infiltration of blood-derived immune cells into the central nervous system (CNS) is the cornerstone of immunopathology in multiple sclerosis (MS). In experimental autoimmune encephalomyelitis (EAE), the animal model of MS, recruitment of immune cells critically depends on the reactivation of autoantigen-specific T cells in the perivascular space of the CNS. The release of inflammatory cytokines by these cells triggers upregulation of the atypical chemokine receptor 3 (ACKR3) on endothelial cells. ACKR3 shuttles the chemokine CXCL12 from the perivascular space to the luminal side of the blood vessel, hereby amplifying the recruitment of immune cells into the CNS. T cell cytokines induce in astrocytes the expression of CXCL12 and ACKR3, which scavenges CXCL12 in non-endothelial cells. ACKR3 and CXCL12, together with other chemokines are also expressed in active MS lesions and the concentration of chemokines in cerebrospinal fluid of patients with MS correlates with disease activity.Consensus exists that chemokine gradients offer the main guidance cues for migrating immune cells. Only limited data are available regarding how such gradients are generated and maintained. In lymph nodes -the best-studied in vivo system- an inter-follicular gradient of CCL21 is actively shaped through localized scavenging of the chemokine by the atypical chemokine receptor 4 (ACKR4). The expression of CXCL12-scavenging ACKR3 in inflamed astrocytes suggests that ACKRs also play an important role in shaping chemokine distribution -and hence immune cell recruitment to sites of inflammation. However, how astrocytic expression of ACKR3 impacts on the distribution of CXCL12 in inflamed CNS tissue remains unknown. It is not known whether inflammatory stimuli induce in astrocytes differential spatio-temporally secretion of chemokines and expression of ACKRs and whether these processes are interlinked at the molecular level. It is my hypothesis that astrocytic ACKR3 shapes CXCL12-gradients during the build-up of CNS inflammation such as emerging MS lesions. I aim to test these hypotheses in the following specific aims:Aim A:Spatio-temporal assessment of ACKR3- expression and CXCL12 distribution during CNS inflammationAim B:Mechanistic assessment of ACKR3-mediated distribution of CXCL12 in inflammation
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