IL-17 controls central nervous system autoimmunity through the intestinal microbiome

Area of Science:

• Neuroimmunology
• Microbiome research
• Autoimmunity

Background:

• T helper 17 (T_H17) cells produce Interleukin-17A (IL-17A) and IL-17F, cytokines implicated in chronic inflammatory diseases like multiple sclerosis and its model, experimental autoimmune encephalomyelitis (EAE).
• The precise role of IL-17A and IL-17F in EAE pathogenesis versus the encephalitogenic capacity of T_H17 cells remains debated.

Purpose of the Study:

• To elucidate the direct versus indirect roles of IL-17A and IL-17F in the development of experimental autoimmune encephalomyelitis (EAE).
• To investigate the influence of IL-17A/F deficiency on gut microbiota composition and its subsequent impact on autoimmunity.

Main Methods:

• Generation of mice deficient in IL-17A and IL-17F.
• Induction of EAE in wild-type and knockout mice.
• Analysis of gut microbiota composition.
• Assessment of T_H17 cell encephalitogenic capacity.
• Reconstitution experiments involving gut microbiota and IL-17A reintroduction.

Main Results:

• Mice deficient for IL-17A/F showed reduced susceptibility to EAE, with altered gut microbiota composition.
• Loss of IL-17A/F in T_H cells did not impair their ability to induce EAE.
• Restoring a normal gut microbiota or reintroducing IL-17A into the gut epithelium of deficient mice reestablished EAE susceptibility.

Conclusions:

• IL-17A and IL-17F are not direct mediators of CNS inflammation in EAE.
• These cytokines function as modulators of intestinal homeostasis, indirectly influencing the development of CNS autoimmunity.
• Gut microbiota alterations play a crucial role in the indirect effects of IL-17A/F on neuroinflammation.