Abstract
The innate immune system represents the host’s first-line defense against pathogens, dead cells or environmental factors. One of the most important inflammatory pathways is represented by the activation of the NOD-like receptor (NLR) protein family. Some NLRs induce the assembly of large caspase-1-activating complexes called inflammasomes. Different types of inflammasomes have been identified that can respond to distinct bacterial, viral or fungal infections; sterile cell damage or other stressors, such as metabolic imbalances. Epigenetic regulation has been recently suggested to provide a complementary mechanism to control inflammasome activity. This regulation can be exerted through at least three main mechanisms, including CpG DNA methylation, histones post-translational modifications and noncoding RNA expression. The repression or promotion of expression of different inflammasomes (NLRP1, NLRP2, NLRP3, NLRP4, NLRP6, NLRP7, NLRP12 and AIM2) through epigenetic mechanisms determines the development of pathologies with variable severity. For example, our team recently explored the role of microRNAs (miRNAs) targeting and modulating the components of the inflammasome as potential biomarkers in bladder cancer and during therapy. This suggests that the epigenetic control of inflammasome-related genes could represent a potential target for further investigations of molecular mechanisms regulating inflammatory pathways.
Highlights
Inflammasomes are cytoplasmic multiprotein complexes sensing microbial pathogens or detecting sterile danger and mediating the activation of proinflammatory cytokines in the context of the innate immune response [1]
It is acknowledged that the basal levels of the inflammasome components are low to prevent inappropriate activation and that two distinct steps are required for the assembly and function of the inflammasome: a first priming step upregulates the levels of inflammasome components, and a second activation step ignites the oligomerization of inflammasome complex [2]
LncRNAs regulate gene expression by interacting with DNA, messenger RNAs and proteins, while miRNAs mediate the post-transcriptional repression or mRNA degradation according to epigenetic mechanisms [11,12]. miRNAs belong to short noncoding RNAs with 22–25 nucleotides in length, and their activity is performed with peculiar complementarity miRNA-mRNAs [12]
Summary
Inflammasomes are cytoplasmic multiprotein complexes sensing microbial pathogens or detecting sterile danger and mediating the activation of proinflammatory cytokines in the context of the innate immune response [1]. Among the transcriptional and post-transcriptional mechanisms that control the levels of inflammasome components in basal and activating conditions [3,4], accumulating evidence indicates that epigenetic events may play a critical role, the failure of which results in the development of pathological conditions, characterized by either hyper- or hypoactivation of the inflammasome. In this review, starting from the definition of the most important epigenetic modifications and their significance, we summarize evidence suggesting their critical role in the regulation of inflammasome activity and inflammasome-related diseases
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