Loss of genome maintenance is linked to mTORC1 signaling and accelerates podocyte damage

• Text
• PDF

Abstract

DNA repair is essential for preserving genome integrity. Podocytes, post-mitotic epithelial cells of the kidney filtration unit, bear limited regenerative capacity, yet their survival is indispensable for kidney health. Podocyte loss is a hallmark of the aging process and of many diseases, but the underlying factors remain unclear. We investigated the consequences of DNA damage in a podocyte-specific knockout mouse model for Ercc1 and in cultured podocytes under genomic stress. Furthermore, we characterized DNA damage-related alterations in mouse and human renal tissue of different ages and patients suffering from minimal change disease and focal segmental glomerulosclerosis. Ercc1 knockout resulted in accumulation of DNA damage, ensuing albuminuria and kidney disease. Podocytes reacted to genomic stress by activating mTORC1 signaling in vitro and in vivo. This was abrogated by inhibiting DNA damage signaling through DNA-PK and ATM kinases and inhibition of mTORC1 modulated the development of glomerulosclerosis. Perturbed DNA repair gene expression and genomic stress in podocytes was also detected in focal segmental glomerulosclerosis. Beyond that, DNA damage signaling occurred in podocytes of healthy aging mice and humans. We provide evidence that genome maintenance in podocytes is linked to the mTORC1 pathway, involved in the aging process and the development of glomerulosclerosis.

Authors

Fabian Braun, Amrei M. Mandel, Linda Blomberg, Milagros N. Wong, Georgia Chatzinikolaou, David H. Meyer, Anna Reinelt, Viji Nair, Roman Akbar-Haase, Phillip J. McCown, Fabian Haas, He Chen, Mahdieh Rahmatollahi, Damian Fermin, Robin Ebbestad, Gisela G. Slaats, Tillmann Bork, Christoph Schell, Sybille Koehler, Paul T. Brinkkoetter, Maja T. Lindenmeyer, Clemens D. Cohen, Martin Kann, David Unnersjö-Jess, Wilhelm Bloch, Matthew G. Sampson, Martijn E.T. Dollé, Victor G. Puelles, Matthias Kretzler, George A. Garinis, Tobias B. Huber, Bernhard Schermer, Thomas Benzing, Björn Schumacher, Christine E. Kurschat

Air pollution and Alzheimer disease phenotype deplete esterified pro-resolving lipid mediator reserves in the brain

• Text
• PDF

Abstract

Background: Traffic-related air pollution (TRAP) is a risk factor for Alzheimer disease (AD), where unresolved brain inflammation has been linked to deficits in the levels of free lipid mediators that enable the resolution of inflammation. It is unknown whether these deficits are due to reductions in esterified lipid pools, the main source of free bioactive pro-resolving lipids in the brain, and whether they are related AD pathophysiology. Methods: This unknown was tested by measuring brain esterified lipid mediators and pathogenic markers of AD in TgF344-AD and wildtype (WT) male and female rats exposed to filtered air or TRAP for 14 months, and in human postmortem pre-frontal cortex of individuals with or without AD. Results: Significant reductions in pro-resolving lipid mediators esterified to neutral lipids and/or phospholipids were seen in AD and TRAP-exposed female rats, where levels were associated with inflammation, synaptic loss and impaired glucose metabolism. Lower esterified pro-resolving lipid mediator concentrations were associated with older age in pre-frontal cortex of humans with AD. Conclusion: Impaired resolution in AD is due to depletion of esterified pro-resolving lipid pools that supply the brain with free bioactive mediators involved in inflammation resolution. TRAP exposure alters the same esterified resolution pathways, reflecting convergent mechanisms underlying AD.

Authors

Ameer Y. Taha, Qing Shen, Yurika Otoki, Nuanyi Liang, Kelley T. Patten, Anthony E. Valenzuela, Christopher D. Wallis, Douglas J. Rowland, Abhijit J. Chaudhari, Keith J. Bein, Anthony S. Wexler, Lee-Way Jin, Brittany N. Dugger, Danielle J. Harvey, Pamela J. Lein

PAI-1 Interaction with Sortilin Related Receptor-1 is Required for Lung Fibrosis

• Text
• PDF

Abstract

Mutation studies of plasminogen activator inhibitor-1 (PAI-1) have previously implied that PAI-1 promotes lung fibrosis via a vitronectin (VTN) dependent mechanism. In the present study, employing two distinct murine fibrosis models and VTN deficient mice, we find that VTN is not required for PAI-1 to drive lung scarring. This result suggested the existence of a profibrotic interaction involving the VTN-binding site on PAI-1 with an unidentified ligand. Using an unbiased proteomic approach, we identified sortilin related receptor 1 (SorLA) as the most highly enriched PAI-1 binding partner in the fibrosing lung. Investigating the role of SorLA in pulmonary fibrosis demonstrated that deficiency of this protein protected against lung scarring in a murine model. We further found that SorLA is required for PAI-1 to promote scarring in mice, that both SorLA and PAI-1 protein levels are increased in human IPF explants, and that these proteins are associated in IPF tissue. Finally, confocal microscopy shows that expression of SorLA in CHO cells increases cell uptake of PAI-1, and these proteins colocalize in the cytoplasm. Together, these data elucidate a mechanism by which the potent profibrotic mediator PAI-1 drives lung fibrosis and implicate SorLA as a potential therapeutic target in IPF treatment.

Authors

Thomas H. Sisson, John J. Osterholzer, Lisa Leung, Venkatesha Basrur, Alexey I. Nesvizhskii, Natalya Subbotina, Mark Warnock, Daniel Torrente, Ammara Q. Virk, Sergey S. Gutor, Jeffrey C. Horowitz, Mary Migliorini, Dudley K. Strickland, Kevin K. Kim, Steven K. Huang, Daniel A. Lawrence

ICOS⁺CD4 T cells define a high susceptibility to anti-PD-1 therapy-induced lung pathogenesis

• Text
• PDF

Abstract

Managing immune-related adverse events (irAEs) caused by cancer immunotherapy is essential for developing effective and safer therapies. However, cellular mechanism(s) underlying organ toxicity during anti-PD-(L)1 therapy remain unclear. Here, we investigated the effect of chronological aging on anti-PD-(L)1 therapy-induced irAE-like lung toxicity, utilizing tumor-bearing aged mice. Anti-PD-(L)1 therapy facilitated ectopic infiltration of T and B cells, and antibody deposition in lung of aged but not young mice. Adoptive transfer of aged lung-derived CD4 T cells into TCR-deficient mice revealed that both pathogenic CD4 T cells and aged host environment were necessary for the irAE-inducible responses. Single-cell transcriptomics of lung-infiltrating cells in aged mice demonstrated that anti-PD-(L)1 therapy elicited ICOS+CD4 T-cell activation. Disruption of ICOS-ICOSL interaction attenuated germinal center B-cell differentiation and subsequent lung damage, which were overcome by local administration of IL-21 in the lung of anti-PD-1 therapy-treated aged mice. Therefore, ICOS+CD4 T cells elicited under aged environment exacerbated aberrant immune responses and the subsequent lung dysfunction. Consistent with the findings from mouse model, ICOS up-regulation in CD4 T cells was associated with later irAE incidence in patients with cancer. These finding will help development of useful strategies for irAE management in cancer patients, many of whom are elderly.

Authors

Mari Yokoi, Kosaku Murakami, Tomonori Yaguchi, Kenji Chamoto, Hiroaki Ozasa, Hironori Yoshida, Mirei Shirakashi, Katsuhiro Ito, Yoshihiro Komohara, Yukio Fujiwara, Hiromu Yano, Tatsuya Ogimoto, Daiki Hira, Tomohiro Terada, Toyohiro Hirai, Hirotake Tsukamoto

Vitamin A-Retinoic Acid Contributes to Muscle Stem Cell and Mitochondrial Function Loss in Old Age

• Text
• PDF

Abstract

Adult stem cells decline in number and function in old age and identifying factors that can delay or revert age-associated adult stem cell dysfunction are vital for maintaining healthy lifespan. Here we show that Vitamin A, a micronutrient that is derived from diet and metabolized into retinoic acid, acts as an antioxidant and transcriptional regulator in muscle stem cells. We first show that obstruction of dietary Vitamin A in young animals drives mitochondrial and cell cycle dysfunction in muscle stem cells that mimics old age. Next, we pharmacologically targeted retinoic acid signaling in myoblasts and aged muscle stem cells ex vivo and in vivo and observed reductions in oxidative damage, enhanced mitochondrial function, and improved maintenance of quiescence through fatty acid oxidation. We next detected the receptor for vitamin A derived retinol, stimulated by retinoic acid 6 or Stra6, was diminished with muscle stem cell activation and in old age. To understand the relevance of Stra6 loss, we knocked down Stra6 and observed an accumulation of mitochondrial reactive oxygen species, as well as changes in mitochondrial morphology and respiration. These results demonstrate that Vitamin A regulates mitochondria and metabolism in muscle stem cells and highlight a unique mechanism connecting stem cell function with vitamin intake.

Authors

Paula M. Fraczek, Pamela Duran, Benjamin A. Yang, Valeria Ferre, Leanne Alawieh, Jesus A. Castor-Macias, Vivian T. Wong, Steve D. Guzman, Celeste Piotto, Klimentini Itsani, Jacqueline A Larouche, Carlos A. Aguilar

The inflammaging microenvironment induces dysfunctional rewiring of Tfh cell differentiation

• Text
• PDF

Abstract

Humoral immunity is orchestrated by follicular helper T (Tfh) cells, which promote cognate B cells to produce high-affinity, protective antibodies. In aged individuals, humoral immunity after vaccination is diminished despite the presence of Tfh cells, suggesting defects after initial Tfh formation. In this study, we utilized both murine and human systems to investigate how aging alters Tfh cell differentiation after influenza vaccination. We found that young Tfh cells underwent progressive differentiation after influenza vaccination, culminating in clonal expansion of effector-like cells in both draining lymph nodes and blood. In aging, early stages of Tfh development occurred normally. However, aging rewired the later stages of development in Tfh cells, resulting in a transcriptional program reflective of cellular senescence, sustained pro-inflammatory cytokine production, and metabolic reprogramming. We investigated the extent to which this rewiring of aged Tfh cells is due to the age-associated inflammatory (“inflammaging”) microenvironment and found that this setting was sufficient to both block the transition of Tfh cells to a post-effector resting state and to skew Tfh cells towards the age-rewired state. Together, these data suggest that aging dampens humoral immunity by cytokine-mediated rewiring of late effector Tfh cell differentiation into an activated, yet less functional, cellular state.

Authors

Cody S. Nelson, Manuel A. Podestà, Maya G. Gempler, Jeong-Mi Lee, Cole J. Batty, Peterson G. Mathenge, Asra Sainju, Matthew R. Chang, Hanzhong Ke, Pragya Chandrakar, Elsa Bechu, Sierra Richardson, Cecilia B. Cavazzoni, Stefan G. Tullius, Reza Abdi, Musie Ghebremichael, Marcia C. Haigis, Wayne A. Marasco, Peter T. Sage

Impact of aging on pulmonary cellular responses during mechanical ventilation

• Text
• PDF

Abstract

Acute respiratory distress syndrome (ARDS) results in significant morbidity and mortality, especially in the elderly. Mechanical ventilation, a common supportive treatment for ARDS, is necessary for maintaining gas exchange, but can also propagate injury. We hypothesized that aging leads to alterations in surfactant function, inflammatory signaling, and microvascular permeability within the lung during mechanical ventilation. Young and aged male mice were mechanically ventilated, and surfactant function, inflammation, and vascular permeability were assessed. Additionally, single-cell RNA sequencing was used to delineate cell-specific transcriptional changes. The results showed that in aged mice, surfactant dysfunction and vascular permeability were significantly augmented, while inflammation was less pronounced. Differential gene expression and pathway analyses revealed that alveolar macrophages in aged mice showed a blunted inflammatory response, while aged endothelial cells exhibited altered cell-cell junction formation. In vitro functional analysis revealed that aged endothelial cells had an impaired ability to form a barrier. These results highlight the complex interplay between aging and mechanical ventilation, including an age-related predisposition to endothelial barrier dysfunction, due to altered cell-cell junction formation, and decreased inflammation, potentially due to immune exhaustion. It is concluded that age-related vascular changes may underlie the increased susceptibility to injury during mechanical ventilation in elderly patients.

Authors

Aminmohamed Manji, Lefeng Wang, Cynthia M. Pape, Lynda A. McCaig, Alexandra Troitskaya, Onon Batnyam, Leah J.J. McDonald, C. Thomas Appleton, Ruud A.W. Veldhuizen, Sean E. Gill

ROCK1 promotes B-cell differentiation and proteostasis under stress through the heme-regulated proteins, BACH2 and HRI

• Text
• PDF

Abstract

The mechanisms utilized by differentiating B cells to withstand highly damaging conditions generated during severe infections, like the massive hemolysis that accompanies malaria, are poorly understood. Here we demonstrate that ROCK1 regulates B cells differentiation in hostile environments replete with PAMPs (pathogen-associated molecular patterns) and high levels of heme by controlling two key heme-regulated molecules, BACH2 and Heme-regulated eIF2a kinase (HRI). ROCK1 phosphorylates BACH2 and protects it from heme-driven degradation. As B cells differentiate, furthermore, ROCK1 restrains their proinflammatory potential and helps them handle the heightened stress imparted by the presence of PAMPs and heme by controlling HRI, a key regulator of the integrated stress response and cytosolic proteotoxicity. ROCK1 controls the interplay of HRI with HSP90 and limits the recruitment of HRI and HSP90 to unique p62/SQSTM1 complexes that also contain critical kinases like mTORC1 and TBK1, and proteins involved in RNA metabolism, oxidative damage, and proteostasis like TDP-43. Thus, ROCK1 helps B cells cope with intense pathogen-driven destruction by coordinating the activity of key controllers of B cell differentiation and stress responses. These ROCK1-dependent mechanisms may be widely employed by cells to handle severe environmental stresses, and these findings may be relevant for immune-mediated and age-related neurodegenerative disorders.

Authors

Juan Rivera-Correa, Sanjay Gupta, Edd Ricker, Danny Flores-Castro, Daniel Jenkins, Stephen Vulcano, Swati P. Phalke, Tania Pannellini, Matthew M. Miele, Zhuoning Li, Nahuel Zamponi, Young-Bum Kim, Yurii Chinenov, Eugenia Giannopoulou, Leandro Cerchietti, Alessandra B. Pernis

Characterization of cognitive decline in long-duration type 1 diabetes by cognitive, neuroimaging and pathological examinations

• Text
• PDF

Abstract

BACKGROUND. We aimed to characterize factors associated with the under-studied complication of cognitive decline in aging people with long-duration type 1 diabetes (T1D). METHODS. Joslin “Medalists” (n = 222; T1D ≥ 50 years) underwent cognitive testing. Medalists (n = 52) and age-matched non-diabetic controls (n = 20) underwent neuro- and retinal imaging. Brain pathology (n = 26) was examined. Relationships amongst clinical, cognitive and neuroimaging parameters were evaluated. RESULTS. Compared to controls, Medalists had worse psychomotor function and recall, which associated with female gender, lower visual acuity, reduced physical activity, longer diabetes duration and higher inflammatory cytokines. On neuroimaging, compared to controls, Medalists had significantly lower total and regional brain volumes, equivalent to 9 years of accelerated aging, but small vessel disease markers did not differ. Reduced brain volumes associated with female sex, reduced psychomotor function, worse visual acuity, longer diabetes duration and higher inflammation, but not with glycemic control. Worse cognitive function, lower brain volumes, and diabetic retinopathy correlated with thinning of the outer retinal nuclear layer. Worse baseline visual acuity associated with declining psychomotor function in longitudinal analysis. Brain volume mediated the association between visual acuity and psychomotor function by 57%. Brain pathologies showed decreased volumes, but predominantly mild vascular or Alzheimer’s-related pathology. CONCLUSION. This first comprehensive study of cognitive function, neuroimaging and pathology in aging T1D individuals demonstrated that cognitive decline was related to parenchymal rather than neurovascular abnormalities, unlike type 2 diabetes, suggestive of accelerated aging in T1D. Improving visual acuity could perhaps be an important preventive measure against cognitive decline in people with T1D.

Authors

Hetal S. Shah, Matthew N. DeSalvo, Anastasia Haidar, Surya Vishva Teja Jangolla, Marc Gregory Yu, Rebecca S. Roque, Amanda Hayes, John Gauthier, Nolan Ziemniak, Elizabeth Viebranz, I-Hsien Wu, Kyoungmin Park, Ward Fickweiler, Tanvi J. Chokshi, Tashrif Billah, Lipeng Ning, Atif Adam, Jennifer K. Sun, Lloyd Paul Aiello, Yogesh Rathi, Mel B. Feany, George L. King

Ageing and inflammation limit the induction of SARS-CoV-2-specific CD8⁺ T cell responses in severe COVID-19

• Text
• PDF

Abstract

CD8+ T cells are critical for immune protection against severe COVID-19 during acute infection with SARS-CoV-2. However, the induction of antiviral CD8+ T cell responses varies substantially among infected people, and a better understanding of the mechanisms that underlie such immune heterogeneity is required for pandemic preparedness and risk stratification. In this study, we analyzed SARS-CoV-2-specific CD4+ and CD8+ T cell responses in relation to age, clinical status, and inflammation among patients infected primarily during the initial wave of the pandemic in France or Japan. We found that age-related contraction of the naive lymphocyte pool and systemic inflammation were associated with suboptimal SARS-CoV-2-specific CD4+ and, even more evidently, CD8+ T cell immunity in patients with acute COVID-19. No such differences were observed for humoral immune responses targeting the spike protein of SARS-CoV-2. We also found that the proinflammatory cytokine IL-18, concentrations of which were significantly elevated among patients with severe disease, suppressed the de novo induction and memory recall of antigen-specific CD8+ T cells, including those directed against SARS-CoV-2. These results potentially explain the vulnerability of older adults to infections that elicit a profound inflammatory response, exemplified by acute COVID-19.

Authors

Gaëlle Autaa, Laura Papagno, Takuto Nogimori, Andrea Boizard-Moracchini, Daniil Korenkov, Maeva Roy, Koichiro Suzuki, Yuji Masuta, Eoghann White, Sian Llewellyn-Lacey, Yasuo Yoshioka, Francesco Nicoli, David A. Price, Julie Dechanet-Merville, Takuya Yamamoto, Isabelle Pellegrin, Victor Appay