TY  - JOUR
AU  - de la Rosa, Clara
AU  - Kendirli, Arek
AU  - Baygün, Seren
AU  - Bauernschmitt, Franz
AU  - Thomann, Anna S
AU  - Kisioglu, Ilgin
AU  - Beckmann, Daniela
AU  - Carpentier Solorio, Yves
AU  - Pfaffenstaller, Veronika
AU  - Tai, Yi-Heng
AU  - Mehraein, Niel
AU  - Sanchez, Paula
AU  - Spieth, Lena
AU  - Gerdes, Lisa Ann
AU  - Beltran, Eduardo
AU  - Dornmair, Klaus
AU  - Simons, Mikael
AU  - Peters, Anneli
AU  - Schmidt-Supprian, Marc
AU  - Kerschensteiner, Martin
TI  - In vivo CRISPR screen reveals regulation of macrophage states in neuroinflammation.
JO  - Nature neuroscience
VL  - 29
IS  - 2
SN  - 1097-6256
CY  - New York, NY
PB  - Nature America
M1  - DZNE-2026-00171
SP  - 493 - 509
PY  - 2026
AB  - Here we established an in vivo CRISPR screening pipeline using genetically editable progenitor cells to dissect macrophage regulation in mouse models of multiple sclerosis (MS). Screening over 100 cytokine receptors and signaling molecules identified interferon-γ, tumor necrosis factor, granulocyte-macrophage colony-stimulating factor and transforming growth factor-β as essential regulators of macrophage polarization in vivo. Single-cell transcriptomics confirmed that transferred progenitor cells generate all blood-derived CNS myeloid cell populations, enabling Perturb-seq analysis of cytokine actions in neuroinflammation. Combined with biosensor expression, our approach allows monitoring cytokine effects on myeloid cell migration, debris phagocytosis and oxidative activity in vivo. Comparative transcriptomic analyses revealed conserved neuroinflammatory cytokine signatures across myeloid populations, CNS compartments and species, elucidating cytokine cues shaping myeloid function in the cerebrospinal fluid and parenchyma of individuals with MS. This versatile pipeline thus provides a scalable framework for high-resolution analysis of macrophage states and uncovers the cytokine signals that underlie their regulation in MS and MS models.
KW  - Animals
KW  - Macrophages: metabolism
KW  - Mice
KW  - Cytokines: metabolism
KW  - Cytokines: genetics
KW  - Mice, Inbred C57BL
KW  - Clustered Regularly Interspaced Short Palindromic Repeats
KW  - Multiple Sclerosis: immunology
KW  - Multiple Sclerosis: genetics
KW  - Humans
KW  - Neuroinflammatory Diseases: genetics
KW  - CRISPR-Cas Systems
KW  - Encephalomyelitis, Autoimmune, Experimental: immunology
KW  - Cytokines (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:41345278
C2  - pmc:PMC12880918
DO  - DOI:10.1038/s41593-025-02151-6
UR  - https://pub.dzne.de/record/285047
ER  -