Knockdown of NEAT1 induces tolerogenic phenotype in dendritic cells by inhibiting activation of NLRP3 inflammasome

Abstract

Rationale: Tolerogenic dendritic cells (tol-DCs) play essential roles in immune-related diseases and induce immune tolerance by shaping T-cell responses. Accumulating evidence suggests that long noncoding RNAs (lncRNAs) play important regulatory roles in the immune system. However, the potential roles and underlying mechanisms of lncRNAs in tol-DCs remain unclear. Methods: RNA in-situ hybridization, histochemistry, and qRT-PCR were performed to determine the distribution and expression of NEAT1 in DCs. Flow cytometry was used to analyze the tolerogenic function of DCs. Small sequencing, followed by bioinformatic analysis, was performed to determine the target genes of NEAT1. The mechanism of NEAT1 was explored using a luciferase reporter, chromatin immunoprecipitation assays, and Immunofluorescence. In-vivo experiments were used to investigate the induction of immune tolerance via NEAT1-knockdown DCs. Results: Our results show that lncRNA NEAT1 can induce tolerogenic phenotype in DCs. Mechanistically, small RNA-seq analysis revealed that NEAT1 knockdown preferentially affected the expression of miR-3076-3p. Furthermore, NEAT1 used the NLRP3 inflammasome as a molecular decoy for miR-3076-3p, thus facilitating the expression of tolerogenic phenotype in DCs. Moreover, the transcription factor E2F1 acted as a repressor of NEAT1 transcription via activity of H3K27ac. Our results also indicate that NEAT1 knockdown in DCs can induce immune tolerance in models of experimental autoimmune myocarditis and heart transplantation. Conclusions: Taken together, our study shows the mechanism used by NEAT1 in inducing tol-DCs and highlights the therapeutic potential of targeting NEAT1 for the treatment of immune-related diseases.

MIR22HG acts as a tumor suppressor via TGFβ/SMAD signaling and facilitates immunotherapy in colorectal cancer

“…A number of lncRNAs have been found to play important roles in immunotherapy. NEAT1 knockdown can induce immune tolerance in vivo and may be a promising therapeutic target in the treatment of immune-related diseases [49]. UCA1 overexpression had been shown to protect PDL1 expression from the repression of miRNAs and contributed to the gastric cancer cells immune escape [50].…”

Leishmania amazonensis Subverts the Transcription Factor Landscape in Dendritic Cells to Avoid Inflammasome Activation and Stall Maturation

“…In conclusion, we describe a new Leishmania immune subversion strategy resulting in stalled DC maturation and pleiotropic inhibition of the TLR/NF-κB/NLRP3 axis, which may have important phenotypic and immunologic consequences: Preventing IL-1β secretion may hamper expansion, survival, and migration of antigen-primed CD4 + and CD8 + T cells, and Th1, Th2, and Th17 differentiation (18,20,121). Indeed, we observed increased transcript expression of cd8a, ly75 (DEC205), jag1, and cd274 in response to L. am infection, suggesting the induction of tolerogenic DCs (122,123), which may favor the differentiation of anergic or regulatory T cells (124,125), thus causing immune suppression and favoring Leishmania infection and immunopathology (126). Our results will incite future studies aimed to characterize the transcriptional landscape and antigen presenting capacity of DCs in vivo that can likely be modulated directly by intracellular Leishmania, indirectly by the uptake of parasite remnants, or by the local immune response, notably pro-(e.g., TNF) and anti-(e.g., IL-10) inflammatory factors produced by bystander cells.…”

Tolerogenic Dendritic Cells: The Pearl of Immunotherapy in Organ Transplantation

“…This kind of IL-10 + DC is characterized by low expression of costimulatory molecules ( 69 ). Nuclear paraspeckle assembly transcript 1 (NEAT1) is proven to use NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasomes as molecular decoys for miR-3076-3p, so knockdown NEAT1 could facilitate the tolerogenic phenotype in DC, which prevents progression of experimental autoimmune myocarditis and induces immune tolerance in a heart transplantation model ( 70 ). The metastasis associated in lung adenocarcinoma transcript 1 (MALAT1) overexpression promotes DC-SIGN expression by functioning as an miR155-5p sponge in the DC cytoplasm, which derives DC to Tol-DC with low expression of costimulatory molecules and high IL-10 secretion, protecting mice from acute rejection after cardiac transplantation ( 71 ).…”