NLRP3 Activation Was Regulated by DNA Methylation Modification duringMycobacterium tuberculosisInfection

Abstract

Mycobacterium tuberculosis (Mtb) infection activates the NLRP3 inflammasome in macrophages and dendritic cells. Much attention has been paid to the mechanisms for regulation of NLRP3 against Mtb. However, whether epigenetic mechanisms participated in NLRP3 activation is still little known. Here we showed that NLRP3 activation was regulated by DNA methylation modification. Mtb infection promoted NLRP3 activation and inflammatory cytokines expression. NLRP3 promoter was cloned and subsequently identified by Dual-Luciferase Reporter System. The results showed that NLRP3 promoter activity was decreased after methylation by DNA methylase Sss I in vitro. Meanwhile, DNA methyltransferases inhibitor DAC could upregulate the expression of NLRP3. Furthermore, promoter region of NLRP3 gene was demethylated after Mtb H37Rv strain infection. These data revealed that DNA methylation was involved in NLRP3 inflammasome activation during Mtb infection and provided a new insight into the relationship between host and pathogens.

CD82 hypomethylation is essential for tuberculosis pathogenesis via regulation of RUNX1-Rab5/22

“…MTB have evolved strategies to promote their survival by dramatically modifying the epigenetic mechanisms of the host cells they infect 42 – 45 . To effectively modulate gene expression within MTB-infected macrophages, MTBs must bring about epigenetic modifications at the appropriate genomic loci.…”

“…Although it is well established that the expression of host genes is affected by epigenetic modification during MTB infection 43 – 45 , new candidates for further development of effective therapeutics against MTB infection are needed 15 , 16 . Recent reports have shown that the NLRP3 promoter region from −700 to −500 bp is demethylated and NLRP3 is subsequently expressed after MTB infection, supporting the hypothesis that MTB targets host NLRP3 for antibacterial host responses via ESAT-6 to activate the NLRP3 inflammasome 26 , 45 .…”

Development of tissue inflammation accompanied by NLRP3 inflammasome activation in rabbits infected with Treponema pallidum strain Nichols

“…NLRP3 is the best-characterized member of the NLR family involved in the innate immune system; this system is activated by exogenous and endogenous stimulatory factors, such as bacteria, viruses, fungi, and components of dying cells [ 5 , 6 ], and NLRP3 serves as a platform for the activation of caspase-1 and the maturation of the pro-inflammatory cytokine IL-1β to engage in the innate immune response [ 7 ]. The role of the NLRP3 inflammasome in pathogenic infections, such as those caused by Pneumococcus [ 8 ], Helicobacter pylori [ 9 ], Neospora caninum [ 10 ], and Mycobacterium tuberculosis [ 11 ] has been demonstrated. However, the involvement of NLRP3 in the inflammatory processes of T. pallidum infection is poorly understood.…”

Interplays between inflammasomes and viruses, bacteria (pathogenic and probiotic), yeasts and parasites

“…Mycobacterium tuberculosis (M. tuberculosis) is a genetically related group of Mycobacterium species that can cause tuberculosis in humans and animals. In 2016, Wei et al [ 47 ] found that M. tuberculosis infection of the human acute monocyte leukaemia cell line THP-1 could promote NLRP3 activation and inflammatory cytokine secretion. The authors discovered that NLRP3 activation was regulated by DNA methylation modification, and DNA methylase Sss I methylation decreased NLRP3 promoter activity.…”

“…The authors discovered that NLRP3 activation was regulated by DNA methylation modification, and DNA methylase Sss I methylation decreased NLRP3 promoter activity. These data suggest that during M. tuberculosis infection, DNA methylation is involved in NLRP3 inflammasome activation [ 47 ]. Clinical M. tuberculosis isolates compared to the laboratory strain H37Rv have been shown to induce lower IL-1β release than H37Rv, suggesting different inflammasome activation abilities.…”