Il-15/il-15rα signalling and synaptic transmission: a crosstalk between the immune and the nervous system?

Immune and nervous system have been traditionally considered separately, but from ‘90s many studies had unraveled the deep interconnection and interdependence between these two systems, enough to coin the term “neuroimmune system” to define this relationship. While it was well known that central nervous system (CNS) actively communicates with the immune system to control immune responses both centrally and peripherally, the opposite action was just recently discovered. Related to the role of immune system in defending and react, the interactions between immune system and CNS have been classically studied in contexts of neuroinflammation such as trauma, injury and disease [1] [2]. Recent evidences about the neuroinflammatory process in non-pathological conditions and the discovery of the important involvement of adaptive immune system in healthy brain development and activity [3], have opened many questions about physiological neuroimmune cross-talk. In this view, the cytokine network, well known to operate in a bidirectional way affecting both immune and nervous system, has a pivotal role in neuroimmune cross-talk [4]. Traditionally seen as immunomodulators, in the last years has been evident that cytokines are also potent neuromodulators [5]. In the complex cytokine system, interleukin 15 (IL-15) is considered a bridge between adaptive and innate immune system and it is one of the first upregulated cytokines in neuroinflammation [6]. It has many bioregulatory roles which range from those of modulator of selected adaptive immune responses [7] [8] and central player in the development and homeostasis of several immunocyte populations [9] to those of a potent, general inhibitor of apoptosis in multiple systems [9]. Interestingly, has been shown that IL-15 and IL-15Rα deletions affect memory and neurotransmitters concentration suggesting a major role of this signalling in cerebral functions which cannot be compensated during the development [10] [11] [12]. IL-15Rα KO mice, in particular, show decreased retention of spatial memory and contextual fear, both related to hippocampus-dependent memory, and alteration in GABA concentration. Their hippocampal ultrastructure is, however, well preserved, suggesting that the modulatory changes may involve neural plasticity even if the exact role of IL15 in modulating neurotransmission has not been investigated so far. The understandings about the mechanism by which IL-15/IL-15Rα system affect the synaptic transmission may be useful to get insight into the mechanisms of cross talk between the immune and the nervous system and eventually to develop strategies to treat pathologies whose symptoms are memory impairments and neuroinflammation.