An Epigenetic Insight into NLRP3 Inflammasome Activation in Inflammation-Related Processes.

Aberrant NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3) inflammasome activation in innate immune cells, triggered by diverse cellular danger signals, leads to the production of inflammatory cytokines (IL-1ß and IL-18) and cell death by pyroptosis. These processes are involved in the pathogenesis of a wide range of diseases such as autoimmune, neurodegenerative, renal, metabolic, vascular diseases and cancer, and during physiological processes such as aging. Epigenetic dynamics mediated by changes in DNA methylation patterns, chromatin assembly and non-coding RNA expression are key regulators of the expression of inflammasome components and its further activation. Here, we review the role of the epigenome in the expression, assembly, and activation of the NLRP3 inflammasome, providing a critical overview of its involvement in the disease and discussing how targeting these mechanisms by epigenetic treatments could be a useful strategy for controlling NLRP3-related inflammatory diseases.

Correction: Increasing TIMP3 expression by hypomethylating agents diminishes soluble MICA, MICB and ULBP2 shedding in acute myeloid leukemia, facilitating NK cell-mediated immune recognition.

[This corrects the article DOI: 10.18632/oncotarget.16657.].

Increasing TIMP3 expression by hypomethylating agents diminishes soluble MICA, MICB and ULBP2 shedding in acute myeloid leukemia, facilitating NK cell-mediated immune recognition.

Acute myeloid leukemia (AML) is a disease with great morphological and genetic heterogeneity, which complicates its prognosis and treatment. The hypomethylating agents azacitidine (Vidaza®, AZA) and decitabine (Dacogen®, DAC) have been approved for the treatment of AML patients, but their mechanisms of action are poorly understood. Natural killer (NK) cells play an important role in the recognition of AML blasts through the interaction of the activating NKG2D receptor with its ligands (NKG2DL: MICA/B and ULBPs1-3). However, soluble NKG2DL (sNKG2DL) can be released from the cell surface, impairing immune recognition. Here, we examined whether hypomethylating agents modulate the release of sNKG2DL from AML cells. Results demonstrated that AZA- and DAC-treated AML cells reduce the release of sNKG2DL, preventing downregulation of NKG2D receptor on the cell surface and promoting immune recognition mediated by NKG2D-NKG2DL engagement. We show that the shedding of MICA, MICB and ULBP2 is inhibited by the increased expression of TIMP3, an ADAM17 inhibitor, after DAC treatment. The TIMP3 gene is highly methylated in AML cells lines and in AML patients (25.5%), in which it is significantly associated with an adverse cytogenetic prognosis of the disease. Overall, TIMP3 could be a target of the demethylating treatments in AML patients, leading to a decrease in MICA, MICB and ULBP2 shedding and the enhancement of the lytic activity of NK cells through the immune recognition mediated by the NKG2D receptor.

Phenotypic characteristics of aged CD4+ CD28null T lymphocytes are determined by changes in the whole-genome DNA methylation pattern.

Aging is associated with a progressive loss of the CD28 costimulatory molecule in CD4+ lymphocytes (CD28null T cells), which is accompanied by the acquisition of new biological and functional properties that give rise to an impaired immune response. The regulatory mechanisms that govern the appearance and function of this cell subset during aging and in several associated inflammatory disorders remain controversial. Here, we present the whole-genome DNA methylation and gene expression profiles of CD28null T cells and its CD28+ counterpart. A comparative analysis revealed that 296 genes are differentially methylated between the two cell subsets. A total of 160 genes associated with cytotoxicity (e.g. GRZB, TYROBP, and RUNX3) and cytokine/chemokine signaling (e.g. CX3CR1, CD27, and IL-1R) are demethylated in CD28null T cells, while 136 de novo-methylated genes matched defects in the TCR signaling pathway (e.g. ITK, TXK, CD3G, and LCK). TCR-landscape analysis confirmed that CD28null T cells have an oligo/monoclonal expansion over the polyclonal background of CD28+ T cells, but feature a Vß family repertoire specific to each individual. We reported that CD28null T cells show a preactivation state characterized by a higher level of expression of inflammasome-related genes that leads to the release of IL-1ß when activated. Overall, our results demonstrate that CD28null T cells have a unique DNA methylation landscape, which is associated with differences in gene expression, contributing to the functionality of these cells. Understanding these epigenetic regulatory mechanisms could suggest novel therapeutic strategies to prevent the accumulation and activation of these cells during aging.