A suppressive oligodeoxynucleotide expressing TTAGGG motifs modulates cellular energetics through the mTOR signaling pathway

Abstract

Immune-mediated inflammation must be down-regulated to facilitate tissue remodeling during homeostatic restoration of an inflammatory response. Uncontrolled or over-exuberant immune activation can cause autoimmune diseases, as well as tissue destruction. A151, the archetypal example of a chemically synthesized suppressive oligodeoxynucleotide (ODN) based on repetitive telomere-derived TTAGGG sequences, was shown to successfully down-regulate a variety of immune responses. However, the degree, duration and breadth of A151-induced transcriptome alterations remain elusive. Here, we performed a comprehensive microarray analysis in combination with Ingenuity Pathway Analysis (IPA) using murine splenocytes to investigate the underlying mechanism of A151-dependent immune suppression. Our results revealed that A151 significantly down-regulates critical mammalian target of rapamycin (mTOR) activators (Pi3kcd, Pdpk1 and Rheb), elements downstream of mTOR signaling (Rps6ka1, Myc, Stat3 and Slc2a1), an important component of the mTORC2 protein complex (Rictor) and Mtor itself. The effects of A151 on mTOR signaling were dose- and time-dependent. Moreover, flow cytometry and immunoblotting analyses demonstrated that A151 is able to reverse mTOR phosphorylation comparably to the well-known mTOR inhibitor rapamycin. Furthermore, Seahorse metabolic assays showed an A151 ODN-induced decrease in both oxygen consumption and glycolysis implying that a metabolically inert state in macrophages could be triggered by A151 treatment. Overall, our findings suggested novel insights into the mechanism by which the immune system is metabolically modulated by A151 ODN.

Inflamm-aging: Why older men are the most susceptible to SARS-CoV-2 complicated outcomes

“…Pilot trials are already in progress [67,68], but a substantial number of potential senolytics with a low toxicity profile have been identified and can safely be explored [69]. Another approach could rely on harnessing the antiinflammatory ability of free telomeric end oligonucleotides [70,71], whose airway administration in aerosol form has been studied in a model of mouse lung injury [72]. This approach would not be limited to elderly COVID-19 patients.…”

A subset of gut leukocytes have telomerase-dependent “hyper-long” telomeres and require telomerase for function in zebrafish

“…When processed during DNA replication, telomeric sequences can bind to cytoplasmic Toll-Like Receptor 9 (TLR9), blocking downstream activation of pro-inflammatory pathways 92 . Indeed, recent work shows that synthetic telomeric sequences can modulate cellular energetics and can shift mice macrophages into a metabolically quiescent state, via mTor regulation 93 .…”

Inflamm-Aging: Why Older Men Are the Most Susceptible to SARS-Cov-2 Complicated Outcomes

“…Pilot trials are already in progress (Hickson et al, 2019;Justice et al, 2019), but a substantial number of potential senolytics with a low toxicity profile have been identified and can safely be explored (Gurau et al, 2018). Another approach could rely on harnessing the anti-inflammatory ability of free telomeric end oligonucleotides (Gursel et al, 2003;Yazar et al, 2020), whose airway administration in aerosol form has been studied in a model of mouse lung injury (Scheiermann and Klinman, 2016). This approach would not be limited to elderly COVID-19 patients.…”