Type 2 immunity in the brain and brain borders

Abstract

Recent research in neuroimmunology has revolutionized our understanding of the intricate interactions between the immune system and the central nervous system (CNS). The CNS, an "immune-privileged organ", is now known to be intimately connected to the immune system through different cell types and cytokines. While type 2 immune responses have traditionally been associated with allergy and parasitic infections, emerging evidence suggests that these responses also play a crucial role in CNS homeostasis and disease pathogenesis. Type 2 immunity encompasses a delicate interplay among stroma, Th2 cells, innate lymphoid type 2 cells (ILC2s), mast cells, basophils, and the cytokines interleukin (IL)-4, IL-5, IL-13, IL-25, TSLP and IL-33. In this review, we discuss the beneficial and detrimental roles of type 2 immune cells and cytokines in CNS injury and homeostasis, cognition, and diseases such as tumors, Alzheimer's disease and multiple sclerosis.

Keywords: Meningeal immunity; Neuroimmunology; Type 2 immunity.

Fig. 1

Neuroimmune circuitry in the brain and borders. Cytokines secreted by mast cells, ILC2s, and Th2s located in the meninges and choroid plexus modulate behavior and learning through receptors expressed by neurons and glia cells. Specifically, IL-4 can mediate its effect directly through the IL-4Rα expressed on GABAergic neurons, and astrocytes, in response to IL-4, produce brain-derived neurotropic factor (BDNF), a key molecule in learning and memory. Th2 cells accumulate in the choroid plexus, resulting in a local excess of IL-4 that acts on choroid plexus epithelial cells to produce CCL11, which has been correlated with the cognitive decline observed during aging. In addition, IL-13-deficient mice exhibit cognitive impairment similar to that observed in IL-4 knockout (KO) mice. IL-13 was also shown to be a synaptic protein in mouse and human brains, localized in the presynaptic membrane, whereas IL-13Rα1 is localized on the postsynaptic membrane. The engagement of IL-13 with type 2 receptors results in the phosphorylation of the NMDAR and AMPAR subunits and increases synaptic activity