Kondhalkar, D. | bioRxiv Science

bioRxiv2023

Cell-free chromatin from dying cells trigger an immune response via the cGAS-STING pathway

It is long established that cell death and immune response are closely related, although the nature of this relationship has remained unclear. We earlier reported that cell-free chromatin particles (cfChPs) released from the billions of cells that die in the body every day to enter into the blood circulation, or those that are released locally from dying cells, can readily enter into healthy cells to induce DNA damage and activate inflammatory cytokines. In this study we investigated whether cfChPs from dying cells might be the missing link between cell death and immune response. We treated human lymphocytes with cfChPs isolated from sera of healthy individuals or with cfChPs released from hypoxia-induced dying lymphocytes. We observed that cfChPs from both sources readily entered into lymphocytes to accumulate in their nuclei within 2 h. This was associated with marked activation of CD69 and release of inflammatory cytokines, as well as of p-STING and cGAS expression. The addition of the STING protein inhibitor H151 to the cfChPs treated cells abolished the release of inflammatory cytokines. These findings lead us to suggest that cfChPs from dying cells are the critical triggers of immune response which act via cGAS-STING pathway.

immunology↗

bioRxiv2022

A pro-oxidant combination of resveratrol and copper down-regulates multiple biological hallmarks of ageing and neurodegeneration

Several hundred billion to a trillion cells die in the body every day, and cell-free chromatin particles (cfChPs) that are released from them enter into the extracellular compartments of the body, including into the circulation. We have earlier reported that cfChPs can readily enter into healthy cells to damage their DNA, activate apoptotic pathways and induce inflammatory cytokines. We hypothesized that repeated lifelong assault on healthy cells by cfChPs is the underlying cause of ageing, and that the ageing process could be retarded by deactivating cfChPs. The latter can be effected by oxygen radicals that are generated upon admixing the nutraceuticals resveratrol (R) and copper (Cu). Using confocal microscopy and antibodies against DNA and histone we detected copious presence of extra-cellular cfChPs in brain of ageing mice, and observed that these were deactivated / eradicated following prolong oral administration of small quantities of R-Cu. Deactivation / eradication of cfChPs was associated with down-regulation of several biological hallmarks of ageing in brain cells which included reduction in: 1) telomere attrition, 2) amyloid deposition, 3) DNA damage, 4) apoptosis, 5) inflammation, 6) senescence, 7) aneuploidy and 8) mitochondrial dysfunction. At a systemic level, R- Cu treatment led to significant reduction in blood levels of glucose, cholesterol and C-reactive protein. These results suggest that cfChPs may be global instigators of ageing and neurodegeneration, and that therapeutic use of R-Cu may help to retard the process of ageing.

neuroscience↗