Anti-TNF-α treatment modulates SASP and SASP-related microRNAs in endothelial cells and in circulating angiogenic cells

Abstract

Endothelial cell senescence is characterized by acquisition of senescence-associated secretory phenotype (SASP), able to promote inflammaging and cancer progression. Emerging evidence suggest that preventing SASP development could help to slow the rate of aging and the progression of age-related diseases, including cancer. Aim of this study was to evaluate whether and how adalimumab, a monoclonal antibody directed against tumor necrosis factor-α (TNF-α), a major SASP component, can prevent the SASP. A three-pronged approach has been adopted to assess the if adalimumab is able to: i) modulate a panel of classic and novel senescence- and SASP-associated markers (interleukin [IL]-6, senescence associated-β-galactosidase, p16/Ink4a, plasminogen activator inhibitor 1, endothelial nitric oxide synthase, miR-146a-5p/Irak1 and miR-126-3p/Spred1) in human umbilical vein endothelial cells (HUVECs); ii) reduce the paracrine effects of senescent HUVECs' secretome on MCF-7 breast cancer cells, through wound healing and mammosphere assay; and iii) exert significant decrease of miR-146a-5p and increase of miR-126-3p in circulating angiogenic cells (CACs) from psoriasis patients receiving adalimumab in monotherapy.TNF-α blockade associated with adalimumab induced significant reduction in released IL-6 and significant increase in eNOS and miR-126-3p expression levels in long-term HUVEC cultures.A significant reduction in miR-146a-5p expression levels both in long-term HUVEC cultures and in CACs isolated from psoriasis patients was also evident. Interestingly, conditioned medium from senescent HUVECs treated with adalimumab was less consistent than medium from untreated cells in inducing migration- and mammosphere- promoting effects on MCF-7 cells.Our findings suggest that adalimumab can induce epigenetic modifications in cells undergoing senescence, thus contributing to the attenuation of SASP tumor-promoting effects.

Premature senescence of endothelial cells upon chronic exposure to TNFα can be prevented by N-acetyl cysteine and plumericin

“…A characteristic feature of cellular senescence is the SASP25262750 involving increased surface expression and release of inflammatory molecules51. In the present work, we chose to assess the expression of the adhesion molecules E-selectin and ICAM-1, as well as of PAI-1, IGFBP-5, IL-6, and IL-8, previously reported to be upregulated in senescence7373839405253.…”

“…It has been established that the underlying cell-cycle arrest is mediated by p21 and p16, two cyclin-dependent kinase inhibitors181920, and that persistent DNA damage signaling drives the hallmark - inflammatory and tumorigenic - phenotype of senescent cells, termed the senescence-associated secretory phenotype (SASP)2122. This SASP, which prominently involves NF-κB signaling2324, comprises adhesion molecules, metalloproteinases, and many cytokines3252627. Some of these, such as IL-1, IL-6, and TNFα, have been implicated in atherosclerosis2829 and diabetes30.…”

MiR-146a-5p correlates with clinical efficacy in patients with psoriasis treated with the tumour necrosis factor-alpha inhibitor adalimumab

“…We have previously reported a significant reduction in miR‐146a‐5p expression levels in circulating angiogenic cells from patients with psoriasis, but the technical complexity of the circulating angiogenic cell isolation protocol precludes its use in clinical practice. Therefore, we focused our current investigation on plasma and peripheral blood mononuclear cells (PBMCs).…”

Update on the mechanisms of action of anti‑TNF-α antibodies and their clinical implications in inflammatory bowel disease

“…An intriguing observation has recently been reported by Prattichizzo et al 52 Analyzing the effect of ADA on senescence of ECs, they have noticed that although inhibition of TNF-α activity by ADA did not delay replicative cell senescence, it did reduce an augmented IL-6 release that is typically associated with the senescent phenotype. The mechanism of this effect is unclear and these observations need to be verified, as ECs have not been typically viewed as a major source of TNF-α.…”