Csf1r-mediated depletion of myeloid cells prevents dopaminergic neuron loss during chronic colitis
Year: 2026
Type: article
Abstract: Inflammatory bowel disease (IBD) predisposes to neuropsychiatric comorbidity and increases the risk of Parkinson’s Disease (PD). Although the gut-immune-brain axis was proposed as a link between IBD and PD and a driver of PD immunopathogenesis, the regional pattern and single-cell landscape of the brain immune response during colitis and its contribution to PD pathology remain poorly defined. Here, we observe a loss of dopaminergic neurons and synuclein pathology in the substantia nigra pars compacta of adult mice with chronic colitis. By confocal microscopy and integrated multi-omics, we reveal a complex midbrain-centered immune response to chronic colitis. Single-cell mapping of the midbrain immune landscape showed an inflammatory shift of microglial clusters including an expansion of interferon-response microglia, CD8 + T cell extravasation, and increased numbers of vessel-associated neutrophils. Selective myeloid cell depletion using a colony stimulating factor 1 receptor (Csf1r) inhibitor after colitis onset reduced midbrain microglia by 67% and led to a complete rescue of dopaminergic neuron loss, without affecting mucosal pathology or T cell and neutrophil migration to the midbrain. Collectively, within the complex midbrain immune response to chronic colitis, we demonstrate a causal role of Csf1r-dependent microglia for dopaminergic neurodegeneration. Thus, Csf1r inhibition in IBD may not locally ameliorate colitis, but provide neuroprotection to dopaminergic neurons. These results reveal a novel cellular link between chronic gut-derived peripheral inflammation and midbrain vulnerability and thereby substantially enhance our understanding of the risk for PD related to the gut-immune-brain axis.
Source: Journal of Neuroinflammation
Authors: Rebecca Katharina Kutscherauer, Marie Andert, Iris Stolzer, Emely Elisa Neumaier, Mark Dedden, Pavel Kielkowski, Wei Xiang, Alexander Grotemeyer, Marco Prinz, Takahiro Masuda, Klaus-Peter Knobeloch, Veit Rothhammer, Sebastian Zundler, Johannes C.M. Schlachetzki, Jürgen Winkler, Claudia Günther, Patrick Süß
Language: English
Subfield: Neurology
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,090
Funders: Uehara Memorial Foundation, Japan Agency for Medical Research and Development, Association of Medical Research Charities, Friedrich-Alexander-Universität Erlangen-Nürnberg, Deutsche Forschungsgemeinschaft, Ministry of Education, Culture, Sports, Science and Technology, Bundesministerium für Bildung und Forschung, Else Kröner-Fresenius-Stiftung, Boehringer Ingelheim Stiftung, Ono Pharmaceutical, Bayerisch-Kalifornischen Hochschulzentrum, Universitätsklinikum Erlangen, Japan Society for the Promotion of Science
Awards: G1014860659, G1037940132, G1177259158, SFB 1181: Schaltstellen zur Auflösung von Entzündung, G1293394741, G1591513776, G1993314343, G2025641821, G259924242, A Paradigm Shift in Anorexia Nervosa: Unveiling the Role of Gut Microbiota and Microglia, G2693943190, G3100021658, Coinhibiotrische Signalwege bei autoimmunentzündlichen Erkrankungen des Zentralnervensystems, G4041520648, G4094968464, G424361051, G4866485077, EXC 2189: CIBSS Centre for Integrative Biological Signalling Studies, G5255665287, G5334289397, G5353614364, KFO 5024: ImmunCheckpoints der Kommunikation zwischen Darm und Gehirn bei entzündlichen und neurodegenerativen Erkrankungen (GB.com), G5597166247, G5976804734, G6184921693, G7063983690, G707554195, iIMMUNE_ACS - Förderung von Advanced Clinician Scientists im Bereich Immunmedizin, G746094396, G7577621542, TRR 274: Kontrollpunkte der ZNS Reparatur, Comprehensive functional analysis of CNS border associted macrophages in brain development, G8624638973
OpenAlex ID: W7166320585