Senescence associated secretory phenotype profile from primary lung mice fibroblasts depends on the senescence induction stimuli

Abstract

Cellular senescence is a multifactorial phenomenon of growth arrest and distorted function, which has been recognized as an important feature during tumor suppression mechanisms and a contributor to aging. Senescent cells have an altered secretion pattern called Senescence-Associated Secretory Phenotype (SASP) that comprises a complex mix of factors including cytokines, growth factors, chemokines, and matrix metalloproteinases. SASP has been related with local inflammation that leads to cellular transformation and neurodegenerative diseases. Various pathways for senescence induction have been proposed; the most studied is replicative senescence due to telomere attrition called replicative senescence (RS). However, senescence can be prematurely achieved when cells are exposed to diverse stimuli such as oxidative stress (stressinduced premature senescence, SIPS) or proteasome inhibition (proteasome inhibition-induced premature senescence, PIIPS). SASP has been characterized in RS and SIPS but not in PIIPS. Hence, our aim was to determine SASP components in primary lung fibroblasts obtained from CD-1 mice induced to senescence by PIIPS and compare them to RS and SIPS. Our results showed important variations in the 62 cytokines analyzed, while SIPS and RS showed an increase in the secretion of most cytokines, and in PIIPS only 13 were incremented. Variations in glutathione-redox balance were also observed in SIPS and RS, and not in PIIPS. All senescence types SASP displayed a pro-inflammatory profile and increased proliferation in L929 mice fibroblasts exposed to SASP. However, the behavior observed was not exactly the same, suggesting that the senescence induction pathway might encompass dissimilar responses in adjacent cells and promote different outcomes.

Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2-independent mechanism

“…In fact, inhibition of MAPKAPK2 by rapamycin has been shown to decrease the levels of pro‐inflammatory cytokines including IL1α, and this effect is highly dependent on mTOR activity (Laberge et al ., 2015; Herranz et al ., 2015). However, we must to understand that the SASP can vary significantly in terms of the quantity and quality of secreted proteins and other factors, depending on the insult used to trigger cell senescence (Maciel‐Baron et al ., 2016; Wiley et al ., 2016); therefore, the composition of the SASP may be vary depending on the tissue and the insult.…”

Human CD8+EMRA T cells display a senescence‐associated secretory phenotype regulated by p38 MAPK

“…We show here the diverse nature of a more differentiated subset of memory cells and postulate that unlike the naïve memory cells, these EMRA cells are an antigen‐experienced functionally senescent population with characteristics of naïve or effector cells generated via different mechanisms. Senescence can be triggered via many routes, and as such, the SASP components also vary; for example, primary lung fibroblasts generated via proteasome inhibition showed a unique combination of SASP constituents compared to the induction of senescence through replication or oxidative stress (Maciel‐Barón et al ., 2016). Ongoing work suggests that the senescent phenotype of our EMRA subset is generated by replicative senescence and homoeostatic mechanisms, but the resulting SASP, while not identical, represents a unique phenotype that is distinct from the other T‐cell subsets.…”

Mitochondria in the spotlight of aging and idiopathic pulmonary fibrosis

“…In the lung, replicative senescence of mouse lung fibroblasts has been shown to induce expression of several inflammatory mediators and growth factors that have the ability to induce proliferation in adjacent cells (74). SASP provokes ER stress and reinforces senescence through autocrine activity rather than by spreading the senescence phenotype to healthy neighboring cells.…”