Abstract
Rett syndrome (RTT) is a progressive neurodevelopmental disorder mainly caused by mutations in the X-linked MECP2 gene. RTT patients show multisystem disturbances associated with an oxinflammatory status. Inflammasomes are multi-protein complexes, responsible for host immune responses against pathogen infections and redox-related cellular stress. Assembly of NLRP3/ASC inflammasome triggers pro-caspase-1 activation, thus, resulting in IL-1β and IL-18 maturation. However, an aberrant activation of inflammasome system has been implicated in several human diseases. Our aim was to investigate the possible role of inflammasome in the chronic subclinical inflammatory condition typical of RTT, by analyzing this complex in basal and lipopolysaccharide (LPS)+ATP-stimulated primary fibroblasts, as well as in serum from RTT patients and healthy volunteers. RTT cells showed increased levels of nuclear p65 and ASC proteins, pro-IL-1β mRNA, and NLRP3/ASC interaction in basal condition, without any further response upon the LPS + ATP stimuli. Moreover, augmented levels of circulating ASC and IL-18 proteins were found in serum of RTT patients, which are likely able to amplify the inflammatory response. Taken together, our findings suggest that RTT patients exhibited a challenged inflammasome machinery at cellular and systemic level, which may contribute to the subclinical inflammatory state feedback observed in this pathology.
Highlights
Rett syndrome (RTT; OMIM identifier #312750), first described by the physician Andreas Rett [1], is a severe neurodevelopmental disorder, predominantly affecting females [2]
nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB)–activating stimulus induces elevated expression of pro-IL-1β, a key pro-inflammatory cytokine involved in the inflammasome pathway [32]
After co-localization analysis, we found that a significant NLRP3ASC interaction was induced by LPS + ATP only in CTR fibroblasts (P < 0.05); while, RTT cells showed a significant increase of inflammasome assembly already in basal condition (P < 0.05; as compared to untreated CTR), and were unable to respond to further challenge with LPS + ATP (Fig. 3B)
Summary
Rett syndrome (RTT; OMIM identifier #312750), first described by the physician Andreas Rett [1], is a severe neurodevelopmental disorder, predominantly affecting females (approx. 1 per 10,000 live births) [2]. The assembly of inflammasomes occurs following the recognition of multiple diverse endogenous and exogenous signals such as “pathogen-associated” or “danger-associated molecular patterns” (PAMPs or DAMPs) by a cytosolic subset of “pattern recognition receptors” (PRRs), named “nucleotide-binding domain and leucine-rich repeat-containing (NLR) proteins” [11]. The activation of these intracellular sensors such as NLRP3, the most widely studied member among them, triggers the oligomerization and the recruitment of the adaptor protein ASC, which in turn is able to recruit the effector protein pro-caspase 1 [12]. The inflammasome pathway is implicated even in the neuroinflammation observed in neurodegenerative disorders, like multiple sclerosis, Alzheimer's and Parkinson's disease [20,21] and in neurodevelopmental pathologies, like autistic spectrum disorders (ASDs) [22]
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