Lymphocyte-mediated neuroprotection in in vitro models of excitotoxicity involves astrocytic activation and the inhibition of MAP kinase signalling pathways

Abstract

It is well established that immunosurveillance is active in the CNS and plays a key role in several CNS disorders but the exact role of immune cells remains elusive. Thus, in the present study we investigated whether lymphocytes are protective/detrimental in in vitro models of excitotoxicty. Kainate (KA)-induced neuronal death was significantly reduced following exposure to mixed lymphocytes or purified T lymphocytes containing either activated or non-activated T-lymphocytes. Conditioned media from lymphocyte preparations, but not boiled conditioned media, was protective against KA-induced toxicity indicating soluble mediators underlie the observed neuroprotection with cytokine arrays indicating IL-16 as the likely candidate. A role for astrocytes was established as the neuroprotection was abolished in the presence of the glial toxin, fluoroacetate. Furthermore, lymphocytes inhibited p38 MAPK and ERK signalling pathways with pharmacological inhibition of these pathways mimicking the protective effect of lymphocytes. Similarly, lymphocytes were neuroprotective against oxygen-glucose deprivation (OGD)-induced cell death with the inhibition of p38 MAPK and ERK signalling pathways involved. These data indicate that lymphocytes are neuroprotective under our experimental conditions and we suggest that astrocytic activation and inhibition of MAPK signalling cascades are involved but further studies are required to investigate whether similar mechanisms underlie the actions of lymphocytes in in vivo experimental models of disease. This article is part of the Special Issue entitled 'The Synaptic Basis of Neurodegenerative Disorders'.

Fingolimod Attenuates Splenocyte-Induced Demyelination in Cerebellar Slice Cultures

“…Next splenocyte-induced demyelination was examined in these organotypic cerebellar slice cultures. We have recently shown that naïve cells isolated from peripheral lymph nodes of wild-type mice are not detrimental to organotypic hippocampal slice cultures, and indeed are neuroprotective against toxicity induced by kainate- and oxygen-glucose deprivation [33]. Accordingly, naïve-splenocytes did not induce any significant change in MBP staining when applied to organotypic cerebellar slice cultures ( Figure 1D ).…”

Microglial homeostasis requires balanced CSF-1/CSF-2 receptor signaling

“…Changes occurring in most neurodegenerative conditions were the high expression of a group of transcripts encoding the lysososmal cathepsin inhibitor Cystatin F (Cst7) (Ma et al, 2011), osteopontin (Spp1), an opsonin for cell debris (Shin et al, 2011), and cholesterol 25-hydroxylase (Ch25h) that, through its product, 25-hydroxycholesterol, activates the LXR pathway and promotes ROS production and inflammation (Jang et al, 2016). Underexpression of neuroprotective (Clec4a1, Il16) (Flytzani et al, 2013, Shrestha et al, 2014 and anti-inflammatory (Klf2, Gramd4, Ddit4, Pirb, Tsc22d3) (Roberts et al, 2017, Ip et al, 2017, Kimura et al, 2015, Zhang et al, 2005, Berrebi et al, 2003 transcripts was observed in ALSP and at least three other conditions ( Fig. 5H).…”

Endogenous recovery after brain damage: molecular mechanisms that balance neuronal life/death fate

“…Nonetheless, their infiltration presumably protects neurons by activating astroglial responses and inhibiting death‐triggering mechanisms such as those driven by p38 (Shrestha et al . ). Infiltrated T cells also assist in tissue recovery after injury.…”

“…In this transient phase termed 'acute phase response' (Anthony et al 2012), immune cells infiltrate into the brain parenchyma, causing further disruption of BBB stability. Nonetheless, their infiltration presumably protects neurons by activating astroglial responses and inhibiting death-triggering mechanisms such as those driven by p38 (Shrestha et al 2014). Infiltrated T cells also assist in tissue recovery after injury.…”