The role of proinflammatory cytokines in cognitive function has been investigated with both beneficial and possible detrimental effects, depending on the cytokine. More recently, the type 2 IL-4 has been demonstrated to play a role in cognition. In this study, using the Morris water maze task, we demonstrate that IL-13–deficient mice are significantly impaired in working memory as well as attenuated reference memory, both functions essential for effective complex learning. During the learning process, wild-type mice increased the number of CD4+ T cells in the meninges and production of IL-13, whereas neither Morris water maze–trained IL-4 nor trained IL-13–deficient mice were able to increase CD4+ T cells in the meninges. Mechanistically, we showed that IL-13 is able to stimulate primary astrocytes to produce brain-derived neurotrophic factor, which does foster cognitive functions. Moreover, Morris water maze–trained wild-type mice were able to increase astrocyte-produced glial fibrillary acidic protein in the hippocampus, which was impaired in Morris water maze–trained IL-4– and IL-13–deficient mice. Collectively, this study strongly suggests that the Th2 cytokines, not only IL-4 but also IL-13, are involved in cognitive functions by stimulating astrocytes from the meninges and hippocampus. These results may be important for future development of therapeutic approaches associated with neurologic disorders such as Parkinson disease–associated dementia and HIV-associated dementia among others.
This work was supported by a Wellcome Trust Clinical Infectious Diseases Research Initiative award and by a South African Medical Research Council career development award (to T.M.B.). This work was also supported by the South African National Research Foundation, the South African Medical Research Council, and by the Department of Science and Technology South African Research Chair Initiative (to F.B.).
The online version of this article contains supplemental material.
Abbreviations used in this article:
- brain-derived neurotrophic factor
- glial fibrillary acidic protein
- Morris water maze
- working memory
- Received September 8, 2016.
- Accepted January 17, 2017.
- Copyright © 2017 by The American Association of Immunologists, Inc.