TY - JOUR T1 - Oxylipin biosynthesis reinforces cellular senescence and allows detection of senolysis. JF - Cell Metab Y1 - 2021 A1 - Wiley, Christopher D A1 - Sharma, Rishi A1 - Davis, Sonnet S A1 - Lopez-Dominguez, Jose Alberto A1 - Mitchell, Kylie P A1 - Wiley, Samantha A1 - Alimirah, Fatouma A1 - Kim, Dong Eun A1 - Payne, Therese A1 - Rosko, Andrew A1 - Aimontche, Eliezer A1 - Deshpande, Sharvari M A1 - Neri, Francesco A1 - Kuehnemann, Chisaka A1 - Demaria, Marco A1 - Ramanathan, Arvind A1 - Campisi, Judith AB -

Cellular senescence is a stress or damage response that causes a permanent proliferative arrest and secretion of numerous factors with potent biological activities. This senescence-associated secretory phenotype (SASP) has been characterized largely for secreted proteins that participate in embryogenesis, wound healing, inflammation, and many age-related pathologies. By contrast, lipid components of the SASP are understudied. We show that senescent cells activate the biosynthesis of several oxylipins that promote segments of the SASP and reinforce the proliferative arrest. Notably, senescent cells synthesize and accumulate an unstudied intracellular prostaglandin, 1a,1b-dihomo-15-deoxy-delta-12,14-prostaglandin J2. Released 15-deoxy-delta-12,14-prostaglandin J2 is a biomarker of senolysis in culture and in vivo. This and other prostaglandin D2-related lipids promote the senescence arrest and SASP by activating RAS signaling. These data identify an important aspect of cellular senescence and a method to detect senolysis.

ER - TY - JOUR T1 - Secretion of leukotrienes by senescent lung fibroblasts promotes pulmonary fibrosis. JF - JCI Insight Y1 - 2019 A1 - Wiley, Christopher D A1 - Brumwell, Alexis N A1 - Davis, Sonnet S A1 - Jackson, Julia R A1 - Valdovinos, Alexis A1 - Calhoun, Cheresa A1 - Alimirah, Fatouma A1 - Castellanos, Carlos A A1 - Ruan, Richard A1 - Wei, Ying A1 - Chapman, Harold A A1 - Ramanathan, Arvind A1 - Campisi, Judith A1 - Jourdan Le Saux, Claude AB -

Accumulation of senescent cells is associated with the progression of pulmonary fibrosis, but mechanisms accounting for this linkage are not well understood. To explore this issue, we investigated whether a class of biologically active profibrotic lipids, the leukotrienes (LT), is part of the senescence-associated secretory phenotype. The analysis of conditioned medium (CM), lipid extracts, and gene expression of LT biosynthesis enzymes revealed that senescent cells secreted LT, regardless of the origin of the cells or the modality of senescence induction. The synthesis of LT was biphasic and followed by antifibrotic prostaglandin (PG) secretion. The LT-rich CM of senescent lung fibroblasts (IMR-90) induced profibrotic signaling in naive fibroblasts, which were abrogated by inhibitors of ALOX5, the principal enzyme in LT biosynthesis. The bleomycin-induced expression of genes encoding LT and PG synthases, level of cysteinyl LT in the bronchoalveolar lavage, and overall fibrosis were reduced upon senescent cell removal either in a genetic mouse model or after senolytic treatment. Quantification of ALOX5+ cells in lung explants obtained from idiopathic pulmonary fibrosis (IPF) patients indicated that half of these cells were also senescent (p16Ink4a+). Unlike human fibroblasts from unused donor lungs made senescent by irradiation, senescent IPF fibroblasts secreted LTs but failed to synthesize PGs. This study demonstrates for the first time to our knowledge that senescent cells secrete functional LTs, significantly contributing to the LT pool known to cause or exacerbate IPF.

VL - 4 IS - 24 ER -