IL-1β enables CNS access to CCR2 hi monocytes and the generation of pathogenic cells through GM-CSF released by CNS endothelial cells
| Autor: | Camille A. Juzwik, Alexandre Prat, Manu Rangachari, Benoit Mailhot, Alyson E. Fournier, Prenitha Mercy Ignatius Arokia Doss, Alexandre Paré, Marc-André Lécuyer, Sébastien A. Lévesque, Steve Lacroix |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Multidisciplinary business.industry Multiple sclerosis Central nervous system Experimental autoimmune encephalomyelitis medicine.disease_cause Spinal cord medicine.disease Blood–brain barrier Autoimmunity 03 medical and health sciences 030104 developmental biology 0302 clinical medicine medicine.anatomical_structure Animal model Immunology medicine business 030217 neurology & neurosurgery Neuroinflammation |
| Zdroj: | Proceedings of the National Academy of Sciences. 115 |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | Molecular interventions that limit pathogenic CNS inflammation are used to treat autoimmune conditions such as multiple sclerosis (MS). Remarkably, IL-1β–knockout mice are highly resistant to experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Here, we show that interfering with the IL-1β/IL-1R1 axis severely impairs the transmigration of myeloid cells across central nervous system (CNS) endothelial cells (ECs). Notably, we report that IL-1β expression by inflammatory CCR2hi monocytes favors their entry into the spinal cord before EAE onset. Following activation with IL-1β, CNS ECs release GM-CSF, which in turn converts monocytes into antigen-presenting cells (APCs). Accordingly, spinal cord-infiltrated monocyte-derived APCs are associated with dividing CD4+ T cells. Factors released from the interaction between IL-1β–competent myeloid cells and CD4+ T cells are highly toxic to neurons. Together, our results suggest that IL-1β signaling is an entry point for targeting both the initiation and exacerbation of neuroinflammation. |
| Databáze: | OpenAIRE |
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