Aging drives organ‐specific alterations of the inflammatory microenvironment guided by immunomodulatory mediators in mice

Schädel, Patrick; Troisi, Fabiana; Czapka, Anna; Gebert, Nadja; Ori, Alessandro; Werz, Oliver

doi:10.1096/fj.202002684r

Cited by 16 publications

(16 citation statements)

References 74 publications

(138 reference statements)

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“…Sterile inflammation has been shown to occur with aging [ 12 ]. This type of inflammatory response is due to immune dysfunction and is closely associated with aging-related organ dysfunction [ 13 ].…”

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confidence: 99%

Role of the cGAS-STING Pathway in Aging-related Endothelial Dysfunction

Yu¹,

Liao²,

Yu³

et al. 2022

Aging and disease

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Endothelial dysfunction develops gradually with age, and is the foundation of many age-related diseases in the elderly. The purpose of this study was to investigate the role of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway in aging-related endothelial dysfunction. Endothelial functional parameters and biochemical indices of vascular function were examined in 2-, 6-, 12- and 24-month-old mice. Then, 6-month-old mice were administered RU.521, a specific inhibitor of cGAS, for 6 months, and endothelial functional parameters and biochemical indices of vascular function were re-examined. An in vitro model of cell senescence was established by treating human aortic endothelial cells (HAECs) with D-Galactose (D-GAL). Using inhibitors or siRNA interference, cGAS and STING were suppressed or silenced in senescent HAECs, and changes in the expression of eNOS, the senescence markers, p53, p21 and p16, components of the cGAS-STING pathway and Senescence-Associated β-galactosidase (SA-β-gal) staining were examined. Finally, cGAS, STING and p-IRF3 levels were measured in aorta tissue sections from eight patients. A decline in endothelial function, up-regulation of p53, p21 and p16 expression, and activation of the cGAS-STING pathway were observed in aging mice. Inhibition of cGAS was found to improve endothelial function and reverse the increased expression of aging markers. Our in vitro data demonstrated that D-GAL induced a decrease in eNOS expression and cell senescence, which could be partly reversed by cGAS inhibitor, STING inhibitor, siRNA-cGAS and siRNA-STING treatment. Higher expression levels of cGAS, STING and p-IRF3 were observed in aged human aortic intima tissue compared to young aortic intima tissue. Our study demonstrated that activation of the cGAS-STING pathway played a vital role in aging-related endothelial dysfunction. Thus, the cGAS-STING pathway may be a potential target for the prevention of cardiovascular diseases in the elderly.

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confidence: 99%

Role of the cGAS-STING Pathway in Aging-related Endothelial Dysfunction

Yu¹,

Liao²,

Yu³

et al. 2022

Aging and disease

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“…Because previous studies on the role of LMs are affected by age, the main strength of this study is the inclusion of patients and HCs of the same age. Age is known to affect LM concentrations 13 and aging is, among other, associated with a deficiency of bioactive LMs such as specialized pro-resolving mediators. 14 By using a cohort of PwMS and HCs of the same age, we have limited the confounding effect of age.…”

Section: Discussionmentioning

confidence: 99%

Association of Arachidonic Acid–Derived Lipid Mediators With Disease Severity in Patients With Relapsing and Progressive Multiple Sclerosis

Broos¹,

Loonstra²,

Ruiter³

et al. 2023

Neurology

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Background and objectives:Excessive activation of certain lipid mediator (LM) pathways play a role in the complex pathogenesis of multiple sclerosis (MS). However, the relation between bioactive LMs and different aspects of CNS-related pathophysiological processes remains largely unknown. Therefore, we here assessed the association of bioactive LMs belonging to the ω-3 / ω-6 lipid classes with clinical, biochemical (serum neurofilament light (sNfL) and serum glial fibrillary acidic protein (sGFAP)) parameters and MRI-based brain volumes in patients with MS (PwMS) and healthy controls (HC).Methods:A targeted high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) approach was used on plasma samples of PwMS and HC of the Project Y cohort, a cross-sectional population based cohort that contains PwMS all born in 1966 in the Netherlands and age-matched HCs. LMs were compared between PwMS and HC and were correlated with levels of sNfL, sGFAP, disability (EDSS) and brain volumes. Finally, significant correlates were included in a backward multivariate regression model to identify which LMs best related to disability.Results:The study sample consisted of 170 patients with relapsing remitting MS (RRMS), 115 patients with progressive MS (PMS) and 125 HC. LM profiles of patients with PMS significantly differed from RRMS and HC, in particular, patients with PMS showed elevated levels of several arachidonic acid (AA) derivatives. In particular 15-HETE (r = 0.24,p< 0.001), positively correlated (average r = 0.2,p< 0.05) with clinical and biochemical parameters such as EDSS and sNfL. In addition, higher 15-HETE levels were related to lower total brain (r = -0.24,p= 0.04) and deep gray matter volumes (r = -0.27,p= 0.02) in patients with PMS and higher lesion volume (r = 0.15,p =0.03) in all PwMS.Discussion:In PwMS of the same birth year, we show that ω-3 and -6 LMs are associated with disability, biochemical (sNfL, GFAP) and MRI measures. Furthermore, our findings indicate that particularly in patients with PMS, elevated levels of specific products of the AA pathway, such as 15-HETE, associate with neurodegenerative processes. Our findings highlight the potential relevance of ω-6 LMs in the pathogenesis of MS.

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“…External standards were used to confirm the retention time, and calibration curves for each analyte were prepared. For quantification of LMs, analyte levels were normalized by calculating the ratio of internal standard and directly measured deuterium-labeled standards to account for loss of analytes during purification and measurement, as reported previously [60], and they were normalized to the protein content of the cells.…”

Section: Lm Analysis By Uplc-ms/msmentioning

confidence: 99%

The Trace Element Selenium Is Important for Redox Signaling in Phorbol Ester-Differentiated THP-1 Macrophages

Wolfram

Weidenbach

Adolf

et al. 2021

IJMS

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Physiological selenium (Se) levels counteract excessive inflammation, with selenoproteins shaping the immunoregulatory cytokine and lipid mediator profile. How exactly differentiation of monocytes into macrophages influences the expression of the selenoproteome in concert with the Se supply remains obscure. THP-1 monocytes were differentiated with phorbol 12-myristate 13-acetate (PMA) into macrophages and (i) the expression of selenoproteins, (ii) differentiation markers, (iii) the activity of NF-κB and NRF2, as well as (iv) lipid mediator profiles were analyzed. Se and differentiation affected the expression of selenoproteins in a heterogeneous manner. GPX4 expression was substantially decreased during differentiation, whereas GPX1 was not affected. Moreover, Se increased the expression of selenoproteins H and F, which was further enhanced by differentiation for selenoprotein F and diminished for selenoprotein H. Notably, LPS-induced expression of NF-κB target genes was facilitated by Se, as was the release of COX- and LOX-derived lipid mediators and substrates required for lipid mediator biosynthesis. This included TXB2, TXB3, 15-HETE, and 12-HEPE, as well as arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). Our results indicate that Se enables macrophages to accurately adjust redox-dependent signaling and thereby modulate downstream lipid mediator profiles.

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Aging drives organ‐specific alterations of the inflammatory microenvironment guided by immunomodulatory mediators in mice

Cited by 16 publications

References 74 publications

Role of the cGAS-STING Pathway in Aging-related Endothelial Dysfunction

Role of the cGAS-STING Pathway in Aging-related Endothelial Dysfunction

Association of Arachidonic Acid–Derived Lipid Mediators With Disease Severity in Patients With Relapsing and Progressive Multiple Sclerosis

The Trace Element Selenium Is Important for Redox Signaling in Phorbol Ester-Differentiated THP-1 Macrophages

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