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bioRxiv · 10.64898/2026.01.23.700559

Csf1r-mediated depletion of midbrain microglia prevents dopaminergic neuron loss during chronic colitis

Kutscherauer, R. K.·Stolzer, I.·Neumaier, E. E.·Dedden, M.·Kielkowski, P.·Xiang, W.·Grotemeyer, A.·Prinz, M.·Masuda, T.·Knobeloch, K.-P.·Rothhammer, V.·Zundler, S.·Schlachetzki, J. C.·Winkler, J.·Guenther, C.·Suess, P.
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Abstract

Inflammatory bowel disease (IBD) predisposes to neuropsychiatric comorbidity and particularly increases the risk of Parkinsons Disease (PD) in later life. 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 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 in comparison to the cortex, hippocampus, and striatum. 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 innate and adaptive 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. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=174 SRC="FIGDIR/small/700559v1_ufig1.gif" ALT="Figure 1"> View larger version (58K): org.highwire.dtl.DTLVardef@1bf7217org.highwire.dtl.DTLVardef@1db66c0org.highwire.dtl.DTLVardef@136ef2eorg.highwire.dtl.DTLVardef@190f641_HPS_FORMAT_FIGEXP M_FIG Graphical abstract. C_FIG

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Kutscherauer, R. K., Stolzer, I., Neumaier, E. E., Dedden, M., Kielkowski, P., Xiang, W., Grotemeyer, A., Prinz, M., Masuda, T., Knobeloch, K.-P., Rothhammer, V., Zundler, S., Schlachetzki, J. C., Winkler, J., Guenther, C., Suess, P.. 2026-01-26. Csf1r-mediated depletion of midbrain microglia prevents dopaminergic neuron loss during chronic colitis. https://doi.org/10.64898/2026.01.23.700559

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