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

• Published in: Nature neuroscience 2023-10, Vol.26 (10), p.1701-1712
• Main Authors: Andreadou, Myrto, Ingelfinger, Florian, De Feo, Donatella, Cramer, Teresa L. M., Tuzlak, Selma, Friebel, Ekaterina, Schreiner, Bettina, Eede, Pascale, Schneeberger, Shirin, Geesdorf, Maria, Ridder, Frederike, Welsh, Christina A., Power, Laura, Kirschenbaum, Daniel, Tyagarajan, Shiva K., Greter, Melanie, Heppner, Frank L., Mundt, Sarah, Becher, Burkhard
• Format: Article
• Language: English
• Subjects: 13/106; 13/31; 13/51; 14/19; 14/32; 38/77; 45/91; 631/250/127; 64/60; 692/699/375/1666; Ablation; Adaptation; Animal Genetics and Genomics; Anti-inflammatory agents; Behavioral Sciences; Biological Techniques; Biomedical and Life Sciences; Biomedicine; Cytokines; Experimental allergic encephalomyelitis; Flow cytometry; Gene sequencing; Immune system; Inflammation; Interleukin 12; Interleukins; Lymphocytes; Lymphocytes T; Multiple sclerosis; Neurobiology; Neurodegeneration; Neuroectoderm; Neurons; Neuroprotection; Neurosciences; Oligodendrocytes; Tissues
• ISSN: 1097-6256; 1546-1726
• DOI: 10.1038/s41593-023-01435-z

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. Interleukin-12 (IL-12) can have anti-inflammatory properties; however, the underlying mechanisms are unclear. Here, the authors show that IL-12-sensing neurons mediate IL-12-induced neuroprotective tissue adaptation in autoimmune conditions of the CNS.