IL-17 controls central nervous system autoimmunity through the intestinal microbiome
- 12 February 2021
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science Immunology
- Vol. 6 (56)
- https://doi.org/10.1126/sciimmunol.aaz6563
Abstract
Interleukin-17A– (IL-17A) and IL-17F–producing CD4+ T helper cells (TH17 cells) are implicated in the development of chronic inflammatory diseases, such as multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). TH17 cells also orchestrate leukocyte invasion of the central nervous system (CNS) and subsequent tissue damage. However, the role of IL-17A and IL-17F as effector cytokines is still confused with the encephalitogenic function of the cells that produce these cytokines, namely, TH17 cells, fueling a long-standing debate in the neuroimmunology field. Here, we demonstrated that mice deficient for IL-17A/F lose their susceptibility to EAE, which correlated with an altered composition of their gut microbiota. However, loss of IL-17A/F in TH cells did not diminish their encephalitogenic capacity. Reconstitution of a wild-type–like intestinal microbiota or reintroduction of IL-17A specifically into the gut epithelium of IL-17A/F–deficient mice reestablished their susceptibility to EAE. Thus, our data demonstrated that IL-17A and IL-17F are not encephalitogenic mediators but rather modulators of intestinal homeostasis that indirectly alter CNS-directed autoimmunity.Keywords
Funding Information
- National Multiple Sclerosis Society (RG-1707-28780)
- FP7 Ideas: European Research Council (Neurokine)
- FP7 Ideas: European Research Council (Neurokine)
- Deutsche Forschungsgemeinschaft (SFB/TRR 128)
- Deutsche Forschungsgemeinschaft (SFB1292)
- Deutsche Forschungsgemeinschaft (SFB/TRR128)
- MINECO (SAF2017-90083-R)
- Swiss National Science Foundation (310030_170320)
- Swiss National Science Foundation (310030_316030)
- Swiss National Science Foundation (310030_150768)
- Deutsche Forschungsgemeinschaft (SFB1292)
- Gemeinnützige Hertie-Stiftung (P1150062)
- Stiftung Rheinland-Pfalz für Innovation (961-386261/1141)
- Deutsche Forschungsgemeinschaft (Reinhart-Koselleck-Grant)
- Deutsche Forschungsgemeinschaft (SFB992)
- Deutsche Forschungsgemeinschaft (SFB1160)
- Deutsche Forschungsgemeinschaft (SFB/TRR 167)
- MINECO (Postdoctoral funding)
- Sobek Foundation
- Sobek Foundation
- Ernst-Jung Foundation
- Ministry of Science, Research and Arts, Baden-Wuerttemberg (Sonderlinie “Neuroinflammation”)
- BMBF-funded competence network (multiple sclerosis (KKNMS))
This publication has 53 references indexed in Scilit:
- Familial transmission rather than defective innate immunity shapes the distinct intestinal microbiota of TLR-deficient miceThe Journal of Experimental Medicine, 2012
- FLASH: fast length adjustment of short reads to improve genome assembliesBioinformatics, 2011
- Proinflammatory T-cell responses to gut microbiota promote experimental autoimmune encephalomyelitisProceedings of the National Academy of Sciences of the United States of America, 2010
- Ironing out the wrinkles in the rare biosphere through improved OTU clusteringEnvironmental Microbiology, 2010
- Global patterns of 16S rRNA diversity at a depth of millions of sequences per sampleProceedings of the National Academy of Sciences of the United States of America, 2010
- Introducing mothur: Open-Source, Platform-Independent, Community-Supported Software for Describing and Comparing Microbial CommunitiesApplied and Environmental Microbiology, 2009
- Induction of Intestinal Th17 Cells by Segmented Filamentous BacteriaCell, 2009
- Enteric Salmonellosis Disrupts the Microbial Ecology of the Murine Gastrointestinal TractInfection and Immunity, 2008
- SILVA: a comprehensive online resource for quality checked and aligned ribosomal RNA sequence data compatible with ARBNucleic Acids Research, 2007
- Naïve Bayesian Classifier for Rapid Assignment of rRNA Sequences into the New Bacterial TaxonomyApplied and Environmental Microbiology, 2007