IL-12 sensing in neurons induces neuroprotective CNS tissue adaptation and attenuates neuroinflammation in mice

Interleukin-12 (IL-12) is a potent driver of type 1 immunity. Paradoxically, in autoimmune conditions, including of the CNS, IL-12 reduces inflammation. The underlying mechanism behind these opposing properties and the involved cellular players remain elusive. Here, we map IL-12 receptor (IL- 12R) expression to NK and T cells as well as neurons and oligodendrocytes. Conditionally ablating the IL-12R across these cell types in adult mice and assessing their susceptibility to experimental autoimmune encephalomyelitis revealed that the neuroprotective role of IL-12 is mediated by neuroectoderm-derived cells, specifically neurons, and not immune cells. In human brain tissue from donors with multiple sclerosis, we observe an IL-12R distribution comparable to mice, suggesting similar mechanisms in mice and humans. Combining flow cytometry, bulk and single-nucleus RNA sequencing, we reveal an IL-12-induced neuroprotective tissue adaption preventing early neurodegeneration and sustaining trophic factor release during neuroinflammation, thereby maintaining CNS integrity in mice. We performed single-nucleus RNA sequencing (Chromium Next GEM Single Cell 3’ Reagent Kits v3.1 protocol, 10X Genomics) of FANS-isolated Hoechst+ nuclei from the cerebellum, brainstem and cervical spinal cord of NestinCre/+Il12rb2fl/fl mice and their Il12rb2fl/fl littermates at steady-state and onset of clinical Experimental Autoimmune Encephalomyelitis (EAE) symptoms (10 days post-immunization). We performed three independent sequencing experiments and successfully sequenced 11 samples.