IL-13–Mediated Regulation of Learning and Memory

Abstract

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.

Lack of interleukin-13 receptor α1 delays the loss of dopaminergic neurons during chronic stress

“…We also collected evidence that IL-13 is produced in both the pars compacta (SNc) and the pars reticularis (SNr) regions of the substantia nigra, and that cellular sources comprises microglia and neurons, including a fraction of TH-positive ones. Neuronal expression of IL-13 was previously reported in the hippocampus and the cortex following an experimental ischemic insult [31, 32], and recent studies suggested a role of this cytokine in cognitive functions [33]. Our findings showed that stress can regulate IL-13 production locally and suggest the intriguing possibility that it may act in a paracrine or, in the case of TH neuron, possibly even in an autocrine fashion.…”

Activation of group 2 innate lymphoid cells alleviates aging-associated cognitive decline

“…They included known ILC2 products such as Areg , Arg1 , and Bmp7 , as well as previously unreported effector molecules such as Vegfc and Lif (Fig. 5, I and J; Brombacher et al, 2017; Chen and Trapp, 2016; Da Mesquita et al, 2018; Davis and Pennypacker, 2018; de Rivero Vaccari et al, 2009; Ito et al, 2019; Kiyota et al, 2018; Monticelli et al, 2016; Nussbaum et al, 2013; Robinette et al, 2015). A number of pro-inflammatory cytokines, such as Il1a , Il1b , Il18 , Il15, and Tnf , were highly expressed by microglia in the aged brain (Fig.…”

“…The mechanisms of immune-mediated cognitive protection are not yet fully understood. Th2 T cell–derived cytokines IL-4 and IL-13 have been shown to preserve spatial learning and memory through reducing inflammation and promoting neurogenesis (Brombacher et al, 2017; Derecki et al, 2010). Regulatory T cells (T reg cells) may also alleviate cognitive decline in mouse models of Alzheimer’s disease, possibly by constraining neuroinflammation (Baruch et al, 2015; Dansokho et al, 2016; Ito et al, 2019).…”

Understanding the functions and relationships of the glymphatic system and meningeal lymphatics

“…More recently, the immune compartment in the meninges was implicated in neuronal function (75). Notably, IL-4 and IL-13 production by meningeal T cells appears to contribute to the maintenance of cognitive function in mice (74,95). Furthermore, production of IFN-γ in the SAS directly regulates social behavior in mice (96).…”