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Gene & Protein in Disease lncRNAs in trained immunity

also present in the nuclei of myeloid-origin cells including the transition of monocytes into macrophages. This
monocytes, monocyte-derived macrophages, and the coordination between transcription factors and lncRNA
monocytic cell line THP-1. Studies have revealed that elucidates the regulatory mechanisms governing myeloid
8,29
the monocytic transcription factor CCAAT-enhancer- cell development. Macrophages display versatility and
binding proteins, binding to the promoter region of the can undergo polarization into distinct subpopulations in
PBOV1 gene via hnRNP-U, regulate the expression of response to environmental cues: the classically activated
NTT. In THP-1 cells, PBOV1 overexpression resulted in macrophages are also called M1-macrophage and
G1 stage cell cycle arrest, decreased CD14 expression, and alternatively activated macrophages or M2-macrophage.
increased CD68 expression, indicating a differentiation IFN-γ or LPS lipopolysaccharide (LPS) stimulation typically
process favoring macrophages. Furthermore, PBOV1 causes M1-like-phenotype, while cytokines IL-4, IL-10,
overexpression led to a significant increase in interleukin or IL-13 induce M2-like phenotypes. Several lncRNAs
(IL)-10 and CXCL10 mRNA levels, along with an involved in macrophage polarization have been identified.
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upregulation of costimulatory molecules. These findings The lncRNA-Cox2 and lncRNA TCONS 00019715 favor
provide compelling evidence of NTT’s pivotal role in M1 polarization, whereas lncRNA LINC00662 favors M2
lineage commitment and the activation of macrophage macrophage polarization in hepatocellular carcinoma
39
cells, underscoring its significance in the intricate (HCC) through Wnt/- catenin pathways. In breast cancer,
regulatory network governing cellular differentiation and the lncRNA BCRT1 and nuclear paraspeckle assembly
immune response activation. 8,27 transcript 1 (NEAT1) enhance the M2-polarization

An additional antisense nuclear lncRNA, recognized of macrophages and astrocyte activation, whereas the
as COX‑2-lncRNA or PACER (P50-associated COX-2 lncRNA-MM2P was found essential for macrophage
40-42
extragenic RNA), is positioned upstream of the COX-2 M2-polarization.
promoter. In a PMA-driven human monocyte-macrophage 2.2. lncRNAs-DC developments
differentiation system, when stimulated with LPS, PACER
expedites the expression of the COX‑2 gene. The evidence lncRNAs play a crucial role in the development and
suggests that PACER accomplishes this by directly functioning of DCs, specialized antigen-presenting cells
sequestering the repressive NF-κB p50 subunit from the that connect innate and adaptive immune responses in
COX-2 promoter. This action enables the formation of the vertebrates. The activities of DCs are intricately regulated by
active p50 – p65 form of NF-κB in the COX-2 promoter various transcription factors, anti-inflammatory cytokines,
region. Moreover, PACER enhances the recruitment of and ncRNAs. Noteworthy lncRNAs such as lnc-DC, HOX
the p300 histone acetyltransferase (HAT) and the RNAP antisense intergenic RNA myeloid 1 (HOTAIRM1), NEAT
II pre-initiation complex. This enhancement leads to 1, and MALAT1 have been identified as key regulators of
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increased histone acetylation, ultimately inducing COX-2 human DC differentiation.
transcription. In summary, PACER assumes a crucial role Long non-coding-DCs are particularly essential
in modulating COX‑2 gene expression by orchestrating in governing the STAT3 pathway, a critical element in
the dynamics of NF-κB subunits and facilitating differentiating human monocytes into DCs. Positioned
the recruitment of key components involved in the between the HOXA1 and HOXA2 genes, HOTAIRM1
transcriptional process. 8,28 undergoes significant histone modifications (H3K4me3
During the differentiation of monocytes into and H3K27me3) in its promoter during the transition
macrophages, a complex series of transcriptional events from monocytes to DCs. An association is suspected
highlights the crucial role of long non-coding monocytic between HOTAIRM1, miR‑3960, and HOXA genes in the
RNA (lnc-MC) and its interaction with the master development of monocyte-dendritic (Mo-DC) cells. The
regulator PU.1. As lnc-MC levels increase in THP-1 cells, downregulation of HOTAIRM1 and HOXA1 expression
8,33
HL-60 cells, and CD34+ hematopoietic stem/progenitor facilitates the transformation of monocytes into DCs.
cells (HSPCs), PU.1 assumes control. It activates lnc-MC The NEAT1, localized in the nucleus, has two isoforms:
production, counteracting miR-199a-5p’s suppression NEAT1‑1 (3.7-kb) and NEAT1‑2 (23-kb). NEAT1‑1
of the lnc-MC promoter and enhancing overall lnc-MC significantly contributes to the tolerogenic phenotype of
expression. This partnership extends its influence to DCs, which are crucial in immunological disorders as they
activin A receptor type 1B (ACVR1B), a crucial protein shape T-cell responses and promote immune tolerance.
in monocyte/macrophage development. In this intricate In addition, NEAT1 in DCs exhibits similarities with the
molecular interplay, the collaboration between PU.1 MALAT1-mediated tolerogenic phenotype, suggesting
and lnc-MC serves as a guiding force, orchestrating collaborative actions among multiple lncRNAs to achieve

Volume 3 Issue 2 (2024) 5 doi: 10.36922/gpd.2791