Neat1 lncRNA organizes the inflammatory gene expressions in the dorsal root ganglion in neuropathic pain caused by nerve injury, 2023, Maruyama et al.

[SNT Gatchaman]

Neat1 lncRNA organizes the inflammatory gene expressions in the dorsal root ganglion in neuropathic pain caused by nerve injury
Maruyama, Motoyo; Sakai, Atsushi; Fukunaga, Tsukasa; Miyagawa, Yoshitaka; Okada, Takashi; Hamada, Michiaki; Suzuki, Hidenori

Primary sensory neurons regulate inflammatory processes in innervated regions through neuro-immune communication. However, how their immune-modulating functions are regulated in concert remains largely unknown.

Here, we show that Neat1 long non-coding RNA (lncRNA) organizes the proinflammatory gene expressions in the dorsal root ganglion (DRG) in chronic intractable neuropathic pain in rats. Neat1 was abundantly expressed in the DRG and was upregulated after peripheral nerve injury. Neat1 overexpression in primary sensory neurons caused mechanical and thermal hypersensitivity, whereas its knockdown alleviated neuropathic pain.

Bioinformatics analysis of comprehensive transcriptome changes indicated the inflammatory response was the most relevant function of genes upregulated through Neat1. Consistent with this, upregulation of proinflammatory genes in the DRG following nerve injury was suppressed by Neat1 knockdown. Expression changes of these proinflammatory genes were regulated through Neat1-mRNA interaction-dependent and -independent mechanisms. Notably, Neat1 increased proinflammatory genes by stabilizing its interacting mRNAs in neuropathic pain. Finally, Neat1 in primary sensory neurons contributed to spinal inflammatory processes that mediated peripheral neuropathic pain.

These findings demonstrate that Neat1 lncRNA is a key regulator of neuro-immune communication in neuropathic pain.

Link | PDF (Frontiers in Immunology)

 

[SNT Gatchaman]

Long non-coding RNAs (lncRNAs) are involved in a wide range of cellular processes and participate in the regulation of gene expression through various mechanisms. Many lncRNAs function as competing endogenous RNAs for microRNAs to indirectly regulate microRNA target genes or as antisense lncRNAs, which are transcribed from the opposite strand of the protein-coding gene, to regulate its host mRNA.

In neuropathic pain, Kcna2 antisense lncRNA decreased the expression of its sense counterpart in primary sensory neurons. However, distinct from prevalent antisense lncRNAs, some lncRNAs have the potential to interact with non-host mRNAs, although little is known about the functional significance of the concurrent regulation of multiple specific targets.

Here, we identified Neat1 lncRNA as a critical regulator of the proinflammatory gene expressions in the DRG including primary sensory neurons in neuropathic pain. Neat1 is generally expressed in the nucleus to regulate gene expression and has a profound role in pathological processes, such as cancer and inflammatory diseases.

We found that Neat1 was upregulated in the DRG to coordinate the expressions of inflammatory genes after peripheral nerve injury through RNA-RNA interaction-dependent and -independent mechanisms. Accordingly, Neat1 was causally involved in neuropathic pain and regulated spinal microglial activation through neuro-immune communication.

 

[Hutan]

I'm just about done for the day, but NEAT1 looks interesting.

See also
The lncRNA Neat1 promotes activation of inflammasomes in macrophages, 2019
Excerpts from the 2019 paper below:

the NLRP3 inflammasome is activated by an extraordinarily diverse array of PAMPs including several viral, bacterial, fungal pathogens, and DAMPs, such as crystalline, particulate (e.g., uric acid crystals, asbestos, and alum), extracellular ATP, pore-forming toxins, as well as change in cellular environment, notably hypoxia

In the current study, we examine lncRNAs that associate with NLRP3 inflammasome in mouse macrophages and identify Neat1 (nuclear enriched abundant transcript 1), a lncRNA transcribed from the multiple endocrine neoplasia locus (hence also known as Men). Neat1 and its human ortholog NEAT1 maintain the structural integrity of the paraspeckles35, a specific type of nuclear bodies in the interchromatin space whose function remains poorly understood36. NEAT1 also regulates the expression of a group of chemokines and cytokines, including IL-6 and CXCL10, through the MAPK pathway37. Of note, the expression of Neat1 is stimulated by many stimuli that also activate inflammasome, including infection of various viruses and some intracellular damages (e.g., ROS) that stabilize hypoxia-inducible factors (HIFs) and the tumor suppressor p5338,39,40.

Our findings establish a direct role for lncRNAs in regulating inflammasomes and suggest that Neat1 may represent a downstream convergence point for inflammasome stimuli.

The assembly of inflammasomes requires a common priming event, such as LPS-induced activation of TLRs, which induces the expression of NLRP3 and pro-IL-1β2,5. However, the NLRC4, AIM2, and especially NLRP3 inflammasomes are versatile inflammasome, collectively responding to a wide range of stimuli5,24,61,62,63,64. It remains unclear whether these stimuli also employ a general mechanism to modulate inflammasomes. Of note, the expression of Neat1 is highly regulated by various signals, including those that activates the tumor suppressor p53 (refs. 40,51). Moreover, hypoxia is a key physiological stressor present within both normal and tumor microenvironments65 and a critical determinant of the immune response. Here we show that Neat1 links the effect of hypoxia with the activation of NLRP3, NLRC4, and AIM2 inflammasomes. Both human NEAT1 and murine Neat1 are thought to maintain the structural integrity of the paraspeckles35, the function of which remains unclear. We find that the paraspeckles are disrupted in response to various inflammasome-activating signals, leading to the release of Neat1 and subsequent translocation to the cytoplasm, implying that paraspeckles may serve as a storage depot for Neat1. Therefore, the upregulation and translocation of Neat1 may be a converging event leading to the activation of the various caspase-1-associated canonical inflammasomes by a wide range of stimuli, underscoring a common mechanism for the assembly of these inflammation signaling platforms. In addition, our finding, along with previous observation that ASC and NLRP3 are recruited from other cellular components to mitochondria and associated endoplasmic reticulum membranes upon both priming and activation processes66, also highlights the trafficking of inflammasome components as a major mechanism for the regulation of inflammasome activity.

Neat1 may represent a therapeutic target for inflammasome-associated diseases such as gout and autoinflammatory syndromes.

 

[Creekside]

More complexity in how out bodies work. The cause of ME will be hard to find if it's due to some obscure molecule that is just the right shape to temporarily bond to a microRNA and thus affect its rate of function. I imagine that in some factory somewhere, parts flowed freely through a chute, but then a small change in the shape of the parts caused them to occasionally lock together in clumps, blocking the chute. Molecular shape is important in biochemistry too.