Journal Article

DZNE-2026-00171

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png In vivo CRISPR screen reveals regulation of macrophage states in neuroinflammation.

de la Rosa, C. ; Kendirli, A. ; Baygün, S. ; Bauernschmitt, F. ; Thomann, A. S. ; Kisioglu, I. ; Beckmann, D. ; Carpentier Solorio, Y. ; Pfaffenstaller, V. ; Tai, Y.-H. ; Mehraein, N. ; Sanchez, P. ; Spieth, L.DZNE* ; Gerdes, L. A. ; Beltran, E. ; Dornmair, K. ; Simons, M.DZNE* ; Peters, A. ; Schmidt-Supprian, M. ; Kerschensteiner, M.

2026
Nature America New York, NY

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Please use a persistent id in citations: doi:10.1038/s41593-025-02151-6

Abstract: 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.

Keyword(s): Animals (MeSH) ; Macrophages: metabolism (MeSH) ; Mice (MeSH) ; Cytokines: metabolism (MeSH) ; Cytokines: genetics (MeSH) ; Mice, Inbred C57BL (MeSH) ; Clustered Regularly Interspaced Short Palindromic Repeats (MeSH) ; Multiple Sclerosis: immunology (MeSH) ; Multiple Sclerosis: genetics (MeSH) ; Humans (MeSH) ; Neuroinflammatory Diseases: genetics (MeSH) ; CRISPR-Cas Systems (MeSH) ; Encephalomyelitis, Autoimmune, Experimental: immunology (MeSH) ; Cytokines

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Contributing Institute(s):

1. Molecular Neurobiology (AG Simons)

Research Program(s):

1. 351 - Brain Function (POF4-351) (POF4-351)

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DEAL Nature ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 25 ; JCR ; National-Konsortium ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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