Shichita, T. et al. Pivotal role of cerebral interleukin-17-producing γδT cells in the delayed phase of ischemic brain injury. Nat. Med. 15, 946–951 (2009).

T lymphocytes that collect at infarction zones within 24 h of a stroke have been suggested to have an important role in the progression of cerebral ischemia–reperfusion (I–R) injury. Japanese researchers now demonstrate for the first time that the interleukin (IL)-23–IL-17 axis is essential for brain inflammation after stroke. “Macrophages infiltrating the site produce IL-23, and IL-17 is produced by γδT cells, not CD4+ helper cells, as previously thought”, confirms senior author Akihiko Yoshimura (Keio University School of Medicine, Tokyo, Japan).

Working with genetically modified mice that were deficient in various interleukins and had an induced I–R injury, the researchers showed that IL-23 expression levels were already elevated within the first day after stroke, but that IL-17 levels did not rise until day 3. The induction of IL-17 production depended on increased IL-23 expression. Use of FTY720, an immunomodulatory prodrug, to block infiltration of T lymphocytes into the brains of mice just after the induction of the brain infarct reduced brain damage compared with controls. Taken together, these findings suggest that IL-23 is active in the immediate stage of I–R brain injury, whereas IL-17 is more important at the stage of delayed I–R injury, when neurons in the penumbra of the brain injury start to show apoptosis.

...this could be the first successful therapy in the subacute phase of brain infarction after stroke

“We are now planning to examine the effect of anti-IL-23 antibody, which is already approved in Canada for patients with psoriasis. It may be that this could be the first successful therapy in the subacute phase of brain infarction after stroke,” predicts Yoshimura. The researchers also intend to direct their efforts to identifying what kind of stimulation increases the expression of IL-23. “It has been shown that TLR4 [Toll-like receptor 4] could be involved in brain ischemia injury. It is highly possible that an endogenous ligand from the injured brain activates TLR4 of the macrophages, thereby stimulating IL-23 secretion. If we can block this process, we will be able to reduce the damage of the brain”, explains Yoshimura.

Another important question is how IL-17 promotes neural cell apoptosis. The current study suggests that IL-17 cannot induce neural cell apoptosis directly, unlike IL-1, which has a more direct toxic effect. “We suspect that IL-17 induces IL-1 from various types of cells. IL-17 may also activate endothelial cells and may also be involved in prostaglandin E2 synthesis,” says Yoshimura. Each process needs to be defined more fully to understand the neurotoxic effect of IL-17.

Although much remains to be done, Yoshmura points out that this study suggests several new potential therapeutic pathways that could help to reduce the secondary inflammation after stroke that promotes brain damage and is sometimes fatal.