Modular inflammation network discovery from large-scale phenotypic screening in genetically heterogeneous mouse brains
The central nervous system (CNS) represents a uniquely immune-privileged environment, with inflammatory responses involving several resident CNS-specific cell types. While stereotyped cellular and transcriptional responses recur across varied diseases, relevant signaling pathways and regulatory networks are not fully understood. Here, we investigate multi-modal inflammatory gene networks at large scale by developing a high-throughput RNA-seq screening and analysis workflow. As proof-of-concept, we investigate genetically heterogeneous mice from a large-scale chemical mutagenesis screen to identify novel functionally relevant variants in six genes previously linked to human CNS disorders: Nrros, Ctsd, Smpd1, Idua, Nlrp1a, and Inpp5d. We leverage the readily interpretable data from our large-scale study to demarcate distinct inflammatory states arising from each mutation. In all, our work provides a validated analysis framework for identifying discrete gene expression modules that are engaged divergently across disease contexts, which can be used to discover novel regulators of CNS neuroimmune homeostasis.
Authors
- Jesse E. Hanson (ORCID: https://orcid.org/0000-0003-3059-5132)
- Edward M. Bertram (ORCID: https://orcid.org/0000-0002-8211-9245)
- Christopher J. Bohlen (ORCID: https://orcid.org/0000-0003-1185-2260)
- Chunli Yan
- Mitchell G. Rezzonico
- Monica Xiong (ORCID: https://orcid.org/0000-0002-8398-1814)
- Carolina Correa-Ospina
- Qixin Bei
- Tracy J. Yuen (ORCID: https://orcid.org/0000-0002-3451-9279)
- Stefan Bauernfried (ORCID: https://orcid.org/0000-0003-1910-5032)
- Brad A. Friedman
- Lucy X. Morris
- Andrew Trujillo
- Mary K. Crow (ORCID: https://orcid.org/0000-0002-7881-2020)
- Lisa A. Miosge (ORCID: https://orcid.org/0000-0001-8317-3377)
- T. Daniel Andrews (ORCID: https://orcid.org/0000-0003-3922-6376)
- Yuanyuan Wang (ORCID: https://orcid.org/0000-0003-1984-1136)
- Yuxin Liang (ORCID: https://orcid.org/0000-0002-1143-423X)
- Zora Modrusan
- Kimberly L. Stark
- Tiffany Cripps
Institutions
- Australian National University (AU)
- Neuroscience Institute (IT)
- Department of Physiological Sciences (RU)
- Institute of Human Genetics (PL)
- Genomic Health (United States) (US)
Publication Details
- Journal
- Journal of Neuroinflammation
- Published
- 2025-09-29
- DOI
- https://doi.org/10.1186/s12974-025-03556-7
- Primary Topic
- Neuroinflammation and Neurodegeneration Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Computational Infrastructure
- Australian National University
- Curtin University of Technology
- Genentech