Abstract
Experimental and clinical evidence have demonstrated aberrant expression of cytokines/chemokines and their receptors in patients with hippocampal sclerosis (HS) and focal cortical dysplasia (FCD). However, there is limited information regarding the modulation of cytokine/chemokine-regulatory networks, suggesting contribution of miRNAs and downstream transcription factors/receptors in these pathologies. Hence, we studied the levels of multiple inflammatory mediators (IL1β, IL1Ra, IL6, IL10, CCL3, CCL4, TNFα and VEGF) along with transcriptional changes of nine related miRNAs and mRNA levels of downstream effectors of significantly altered cytokines/chemokines in brain tissues obtained from patients with HS (n = 26) and FCD (n = 26). Up regulation of IL1β, IL6, CCL3, CCL4, STAT-3, C-JUN and CCR5, and down regulation of IL 10 were observed in both HS and FCD cases (p < 0.05). CCR5 was significantly up regulated in FCD as compared to HS (p < 0.001). Both, HS and FCD presented decreased miR-223-3p, miR-21-5p, miR-204-5p and let-7a-5p and increased miR-155-5p expression (p < 0.05). As compared to HS, miR-204-5p (upstream to CCR5 and IL1β) and miR-195-5p (upstream to CCL4) were significantly decreased in FCD patients (p < 0.01). Our results suggest differential alteration of cytokine/chemokine regulatory networks in HS and FCD and provide a rationale for developing pathology specific therapy.
Highlights
Induced inflammatory response in FCD is supported by the activation of IL6 and IL1β signalling pathways, induction of the chemokines, microglial reactivity, as well as blood brain barrier (BBB) breakdown[9,10]
We measured the level of eight inflammatory mediators (IL1β, IL1Ra, IL6, IL10, CCL3(MIP1α), CCL4(MIP1β), TNFα and vascular endothelial growth factor (VEGF)) and investigated the gene expression of nine inflammation-related miRNAs and four downstream effectors (STAT-3, C-JUN, ICER and CCR5) in brain tissues obtained from fifty two epilepsy patients and twenty two non-epileptic control subjects using multiplex immunoassay and quantitative RT-PCR respectively
A number of altered molecules are common in both pathologies, but differential expression of CCR5, miR-204 and miR-195 are demonstrated in FCD
Summary
Induced inflammatory response in FCD is supported by the activation of IL6 and IL1β signalling pathways, induction of the chemokines, microglial reactivity, as well as blood brain barrier (BBB) breakdown[9,10]. Little is known regarding the postulated cytokine/ chemokine regulatory network in HS and FCD; inflammation related mediators have been implicated in a number of studies. The aim of the present study was to analyze the cytokine-chemokine regulatory networks in the brain tissues resected from patients with HS and FCD. We measured the level of eight inflammatory mediators (IL1β, IL1Ra, IL6, IL10, CCL3(MIP1α), CCL4(MIP1β), TNFα and VEGF) and investigated the gene expression of nine inflammation-related miRNAs (miR-106a-5p, miR-223a-3p, miR-21-5p, miR-195-5p, miR-204-5p, miR-203-3p, miR-155-5p, let-7a-5p and let-7c-5p) and four downstream effectors (STAT-3, C-JUN, ICER and CCR5) in brain tissues obtained from fifty two epilepsy patients (twenty six HS and twenty six FCD) and twenty two non-epileptic control subjects using multiplex immunoassay and quantitative RT-PCR respectively. The inflammatory mediators and the downstream effectors were selected based on previous literatureand contribution in inflammatory processes[13,14,15,16,17,18] whereas miRNAs were identified through miRTarBase[19]
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