Spatiotemporal analysis of macrophages in neuroinflammatory lesions 2259964

Abstract

Abstract Introduction During neuroinflammation such as multiple sclerosis (MS), macrophages infiltrate into the CNS and act as important drivers and regulators of inflammation. CNS-associated macrophages are highly plastic and perform diverse functions in neuroinflammation; they can mediate either pro- or anti-inflammatory effects. However, while it is becoming clear that multiple macrophage states exist, the origin and basis of the functional heterogeneity of macrophages is poorly understood. Methods To shed light on macrophage functional heterogeneity during neuroinflammation, we performed matched single-cell RNA-sequencing and spatial transcriptomics of immune infiltrates in evolving neuroinflammatory lesions in mice. Results We identified distinct macrophage subpopulations that appear at different stages of inflammation and express unique transcriptional profiles. By performing spatial co-localization and cell-cell-interaction analysis, we identified these different macrophage populations to mediate distinct functions in the neuroinflammatory lesions. To validate functional roles of specific macrophage cell-cell interactions we are performing CRISPR/Cas9 spatial screening. Conclusion We believe that our results improve our understanding of macrophage functional diversity and reveal fundamental processes underlying macrophage heterogeneity and, more importantly, have the potential to identify new biomarkers and actionable targets that could be exploited for targeted modulation of macrophages to improve the outcome of MS. Funding Source n/a Topic Categories Neuroimmunology (NEUR)