microRNA-142–mediated repression of phosphodiesterase 3B critically regulates peripheral immune tolerance, 2019, Lord et al

[Andy]

Tregs play a fundamental role in immune tolerance via control of self-reactive effector T cells (Teffs). This function is dependent on maintenance of a high intracellular cAMP concentration. A number of microRNAs are implicated in the maintenance of Tregs.

In this study, we demonstrate that peripheral immune tolerance is critically dependent on posttranscriptional repression of the cAMP-hydrolyzing enzyme phosphodiesterase-3b (Pde3b) by microRNA-142-5p (miR-142-5p). In this manner, miR-142-5p acts as an immunometabolic regulator of intracellular cAMP, controlling Treg suppressive function. Mir142 was associated with a super enhancer bound by the Treg lineage–determining transcription factor forkhead box P3 (FOXP3), and Treg-specific deletion of miR-142 in mice (TregΔ142) resulted in spontaneous, lethal, multisystem autoimmunity, despite preserved numbers of phenotypically normal Tregs. Pharmacological inhibition and genetic ablation of PDE3B prevented autoimmune disease and reversed the impaired suppressive function of Tregs in TregΔ142 animals.

These findings reveal a critical molecular switch, specifying Treg function through the modulation of a highly conserved, cell-intrinsic metabolic pathway. Modulation of this pathway has direct relevance to the pathogenesis and treatment of autoimmunity and cancer.

Open access at https://www.jci.org/articles/view/124725

Press release about the paper

Masterswitch discovered in body’s immune system

Scientists have discovered a critical part of the body’s immune system with potentially major implications for the treatment of some of the most devastating diseases affecting humans.

Professor Graham Lord, from The University of Manchester, led the study, which could translate into treatments for autoimmune diseases including Cancer, Diabetes, Multiple Sclerosis and Crohn’s Disease within a few years.

It is published in The Journal of Clinical Investigation today.

The discovery of the molecular pathway regulated by a tiny molecule - known as microRNA-142 - is a major advance in our understanding of the immune system.

https://www.manchester.ac.uk/discover/news/masterswitch-discovered-in-bodys-immune-system/

 

[wigglethemouse]

Very interesting. We have multiple groups looking at miRNA's in ME/CFS. Maybe something comes of it.

High-throughput sequencing of plasma microRNA in chronic fatigue syndrome/myalgic encephalomyelitis (2014 Marshall-Gradisnik et al)
https://www.ncbi.nlm.nih.gov/pubmed/25238588

RESULTS:

Using Illumina high-throughput sequencing we identified 19 miRNAs that were differentially expressed in the plasma of CFS/ME patients in comparison to non-fatigued controls. Following RT-qPCR analysis, we were able to confirm the significant up-regulation of three miRNAs (hsa-miR-127-3p, hsa-miR-142-5p and hsa-miR-143-3p) in the CFS/ME patients.

 

[Andy]

I'm way way out of my depth here but it seems to me this paper might be talking about what is hypothesised in the paper linked to in this thread, https://s4me.info/threads/myalgic-e...ss-develop-2019-g-morris-maes-berk-puri.8143/

Or at least in the same ball park...possibly.

 

[Suffolkres]

Merged thread

https://www.sciencedaily.com/releas...KbL4XHDH-OcMjMJ-El1PxEHzJlkvUGG9NfIph0678hmlI

Source:
University of Manchester
Summary:
Scientists have discovered a critical part of the body's immune system with potentially major implications for the treatment of some of the most devastating diseases affecting humans. The study could translate into treatments for autoimmune diseases including Cancer, Diabetes, Multiple Sclerosis and Crohn's Disease within a few years.

 

[Hutan]

We now have two studies of people with ME/CFS that have found mir-142-5p to be up-regulated:
High-Throughput Sequencing of Plasma MicroRNA in CFS/ME, 2014, Brenu, Staines, Marshall-Gradisnik et al (mentioned up-thread by @wigglethemouse), and

Circulating miRNAs Expression in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome 2023 Soffritti et al

 

[Hutan]

miR-142-5p expression is downregulated in CD4+ T cells from patients with the multisystem autoimmune disease systemic lupus erythematosus (SLE) compared with healthy controls and overexpressed in an animal model of multiple sclerosis, suggesting that miR-142 plays a role in autoimmune disease (19, 20).

In this study, we show that miR-142-5p directly targets phosphodiesterase-3b (Pde3b) mRNA, limiting PDE3B protein levels in Tregs. PDE3B hydrolyzes its substrates cAMP and 3′-5′-cyclic guanine monophosphate (cGMP) to AMP and GMP, respectively, thus accelerating intracellular cAMP and cGMP turnover (21). The suppressive function of Tregs is critically dependent on the intracellular concentration of cAMP (22), with Tregs maintaining high levels of intracellular cAMP and Teffs requiring low cAMP levels to undergo activation (23). Collectively, our findings reveal a critical role for miR-142-5p in the regulation of intracellular cAMP concentration via modulation of Pde3b expression in Tregs and therefore place miR-142-5p in the center of the molecular circuitry that regulates Treg suppressive function.

Following our analysis, the only miRNA gene associated with a Foxp3 super-enhancer in Tregs was Mir142, located approximately 2 kb upstream of the fifth ranked Foxp3-associated super-enhancer (Figure 1A and Table 1). FOXP3 bound this locus both in thymically derived Tregs analyzed directly ex vivo (tTreg) and in Tregs induced in vitro from naive CD4+ T cells activated in the presence of TGF-β and IL-2 (iTreg) (Figure 1A). The Mir142 locus was also associated with high levels of histone H3 lysine-4 tri-methylation (H3K4me3) in both tTreg and iTreg and was transcriptionally active (Figure 1A). These data suggest that miR-142 is important for Treg function.

We have seen some mention of Foxp3 in ME/CFS studies.

 

[Hutan]

Re the Foxp3 mentions, see for example this study recently funded by the NIH related to the outcome of exhausted CD8+ T cells:
NIH $2.5M R01 grant to Drs Liisa Selin and Anna Gil for their work on altered T cells in ME/CFS, 2021

Previous studies focused on perturbation in cytokines and metabolism have also shown that CD8 T responses are decreased in ME/CFS. In preliminary studies we examined the frequency, functional and phenotypic status of CD8 T cells to determine whether they were altered in chronic ME/CFS donors as compared to healthy donors. We observed an increased CD4:CD8 ratio, altered expression of exhaustion/activation markers like CTLA4 and 2B4 on CD8 T cells, and decreased production of IFN, TNF and CD107a/b upregulation following PMA stimulation, all suggesting CD8 T cell exhaustion. This was associated with a, perhaps compensatory increased frequency of activated CD4+CD8+ T cells in the ME/CFS donors as compared to healthy controls. Notably, a subset of the CD8 and the CD4+CD8+ T cell populations were spontaneously producing atypical cytokines, subdividing ME/CFS donors into two subsets: type 1 had an increased frequency of FoxP3+helios+ Treg-like cells producing IL9 (female donors); type 2 had FoxP3+helios- cells producing IL17 (male donors). When we examined the T-cell receptor (TCR) repertoire of the CD4+CD8+ T cell population we found evidence of antigen driven clonal expansions to an unknown antigen at this time, whether it will be a viral or auto-antigen.

We hypothesize that the common theme in ME/CFS is an aberrant response to an immunological trigger like infection, which results in a permanently dysregulated immune system as a result of CD8 T cell exhaustion. These studies will identify potential biomarkers and mechanisms driving the immunopathogenesis of ME/CFS leading to future therapies. We will explore this hypothesis in the following Aims.

There's a paper that joins dots between increased serum exosomal miR-142-5p and CD8+ T cell exhaustion, via lymphatic endothelial cells and IDO activity (as in IDO1).

 

[Hutan]

There's a paper that suggests that a viral infection increases miR-142-5p and that that increase can favour the virus by decreasing apoptosis.
Rotavirus-induced miR-142-5p elicits proviral milieu by targeting non-canonical transforming growth factor beta signalling and apoptosis in cells

Furthermore, RV NSP5[the rotavirus] was identified to modulate the expression of hsa-miR-142-5p and confer viral propagation by blocking non-canonical transforming growth factor beta (TGFβ) signalling and the resulting apoptosis.