bims-imseme 2023-11-05 papers

Issue of 2023‒11‒05
nine papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Biogerontology. 2023 Nov 02.

T-cell lymphocytes' aging clock: telomeres, telomerase and aging.

Alain Chebly, Charbel Khalil, Alexandra Kuzyk, Marie Beylot-Barry, Edith Chevret.

Aging is the decline of physiological capabilities required for life maintenance and reproduction over time. The human immune cells, including T-cells lymphocytes, undergo dramatic aging-related changes, including those related to telomeres and telomerase. It was demonstrated that telomeres and telomerase play crucial roles in T-cell differentiation, aging, and diseases, including a well-documented link between short telomeres and telomerase activation demonstrated in several T-cells malignancies. Herein, we provide a comprehensive review of the literature regarding T-cells' telomeres and telomerase in health and age related-diseases.

Keywords: Aging; Disease; Health; Lymphocytes; Lymphomagenesis; T-cell; TERT; Telomerase; Telomeres

DOI: https://doi.org/10.1007/s10522-023-10075-6

Exp Mol Med. 2023 Nov 01.

CD8 T-cell subsets: heterogeneity, functions, and therapeutic potential.

Choong-Hyun Koh, Suyoung Lee, Minkyeong Kwak, Byung-Seok Kim, Yeonseok Chung.

CD8 T cells play crucial roles in immune surveillance and defense against infections and cancer. After encountering antigenic stimulation, naïve CD8 T cells differentiate and acquire effector functions, enabling them to eliminate infected or malignant cells. Traditionally, cytotoxic T cells, characterized by their ability to produce effector cytokines and release cytotoxic granules to directly kill target cells, have been recognized as the constituents of the predominant effector T-cell subset. However, emerging evidence suggests distinct subsets of effector CD8 T cells that each exhibit unique effector functions and therapeutic potential. This review highlights recent advancements in our understanding of CD8 T-cell subsets and the contributions of these cells to various disease pathologies. Understanding the diverse roles and functions of effector CD8 T-cell subsets is crucial to discern the complex dynamics of immune responses in different disease settings. Furthermore, the development of immunotherapeutic approaches that specifically target and regulate the function of distinct CD8 T-cell subsets holds great promise for precision medicine.

DOI: https://doi.org/10.1038/s12276-023-01105-x

Trends Cell Biol. 2023 Oct 31. pii: S0962-8924(23)00207-6. [Epub ahead of print]

Mitochondrial regulation in stem cells.

Yifei Wang, Marine Barthez, Danica Chen.

Stem cells persist throughout the lifespan to repair and regenerate tissues due to their unique ability to self-renew and differentiate. Here we reflect on the recent discoveries in stem cells that highlight a mitochondrial metabolic checkpoint at the restriction point of the stem cell cycle. Mitochondrial activation supports stem cell proliferation and differentiation by providing energy supply and metabolites as signaling molecules. Concomitant mitochondrial stress can lead to loss of stem cell self-renewal and requires the surveillance of various mitochondrial quality control mechanisms. During aging, a mitochondrial protective program mediated by several sirtuins becomes dysregulated and can be targeted to reverse stem cell aging and tissue degeneration, giving hope for targeting the mitochondrial metabolic checkpoint for treating tissue degenerative diseases.

Keywords: NAD; NLRP3; SIRT2; SIRT3; SIRT7; aging

DOI: https://doi.org/10.1016/j.tcb.2023.10.003

Ann Med Surg (Lond). 2023 Nov;85(11): 5511-5522

Unveiling the growing significance of metabolism in modulating immune cell function: exploring mechanisms and implications; a review.

Nicholas Aderinto, Muili Opeyemi Abdulbasit, Adrien Djabo Eric Tangmi, John Olalekan Okesanya, Jolayemi Mustapha Mubarak.

Immunometabolism has emerged as a rapidly growing field of research, holding significant promise for personalised medicine and precision immunotherapy. This review explores the intricate relationship between immune function and metabolic processes, emphasising their profound impact on various immune-related disorders. Understanding how metabolic dysregulation contributes to the pathogenesis of these disorders remains a critical research gap. Therefore, this review aims to bridge that gap by examining the key metabolic pathways involved and their specific implications in immune cell function. Key metabolic pathways, including glycolysis, mitochondrial metabolism, fatty acid metabolism, and amino acid metabolism, are discussed in the context of immune cell function. Dysregulation of these pathways can disrupt immune cell activation, differentiation, and overall function, contributing to disease pathogenesis. Understanding these metabolic alterations' molecular mechanisms is essential for developing targeted therapeutic interventions. The review also emphasises the importance of personalised medicine in immune-related disorders. The unique metabolic profiles of individuals can influence treatment outcomes, highlighting the need for tailored approaches. Integrating metabolic profiling into clinical practice can enhance treatment efficacy and improve patient outcomes. Investigating the clinical significance of immunometabolism in diverse disease contexts will facilitate the translation of research findings into clinical practice. Moreover, refining treatment strategies based on individual metabolic profiles will contribute to advancing precision immunotherapy.

Keywords: immunometabolism; metabolic dysregulation; metabolism

DOI: https://doi.org/10.1097/MS9.0000000000001308

J Nutr Biochem. 2023 Oct 26. pii: S0955-2863(23)00241-3. [Epub ahead of print] 109508

Dietary leucine supplementation restores T-cell mitochondrial respiration and regulates T-lineage differentiation in denervation-induced sarcopenic mice.

Shuang Liu, Marii Mochizuki, Yasuyuki Suzuki, Erika Takemasa, Akiko Yano, Matome Imai, Masaki Mogi.

With the aim of offsetting immune dysfunction preceded by sarcopenia, the feasibility and efficiency of nutritional leucine supplementation were evaluated using a murine denervation-induced sarcopenia model. Sciatic nerve axotomy caused significant loss of skeletal muscle of the hind limbs and accelerated mitochondrial stress along with suppressed ATP production in spleen-derived T cells. Dietary leucine intake not only ameliorated muscle mass anabolism in a sarcopenic state, but also restored mitochondrial respiratory function, as indicated by elevated levels of basal respiration, maximal respiration, spare respiratory capacity, and ATP production, in T cells, which in turn led to downregulated expression of mTOR and downstream signals, as indicated by the findings of comprehensive transcriptome analysis. Consequentially, this finally resulted in amelioration of the sarcopenia-induced relative Th1/Th17-dominant proinflammatory microenvironment. These results highlight the importance of leucine-promoted metabolic cues in directing T cell fate in a sarcopenic microenvironment. The present study provides insights that particularly help rationalize the design and optimization of leucine supplementation for chronic sarcopenic patients with autoimmune disease.

Keywords: Leucine; RNA-seq; Sarcopenia; T cell; mitochondria

DOI: https://doi.org/10.1016/j.jnutbio.2023.109508

Nat Metab. 2023 Oct 30.

PDK4-dependent hypercatabolism and lactate production of senescent cells promotes cancer malignancy.

Xuefeng Dou, Qiang Fu, Qilai Long, Shuning Liu, Yejun Zou, Da Fu, Qixia Xu, Zhirui Jiang, Xiaohui Ren, Guilong Zhang, Xiaoling Wei, Qingfeng Li, Judith Campisi, Yuzheng Zhao, Yu Sun.

Senescent cells remain metabolically active, but their metabolic landscape and resulting implications remain underexplored. Here, we report upregulation of pyruvate dehydrogenase kinase 4 (PDK4) upon senescence, particularly in some stromal cell lines. Senescent cells display a PDK4-dependent increase in aerobic glycolysis and enhanced lactate production but maintain mitochondrial respiration and redox activity, thus adopting a special form of metabolic reprogramming. Medium from PDK4+ stromal cells promotes the malignancy of recipient cancer cells in vitro, whereas inhibition of PDK4 causes tumor regression in vivo. We find that lactate promotes reactive oxygen species production via NOX1 to drive the senescence-associated secretory phenotype, whereas PDK4 suppression reduces DNA damage severity and restrains the senescence-associated secretory phenotype. In preclinical trials, PDK4 inhibition alleviates physical dysfunction and prevents age-associated frailty. Together, our study confirms the hypercatabolic nature of senescent cells and reveals a metabolic link between cellular senescence, lactate production, and possibly, age-related pathologies, including but not limited to cancer.

DOI: https://doi.org/10.1038/s42255-023-00912-w

Cancer Immunol Immunother. 2023 Nov 03.

Cholesterol induction in CD8+ T cell exhaustion in colorectal cancer via the regulation of endoplasmic reticulum-mitochondria contact sites.

Han Shuwen, Wu Yinhang, Zhuang Jing, Yan Qiang, Jiang Yizhen, Qi Quan, Jin Yin, Liu Jiang, Yang Xi.

BACKGROUND: Hypercholesterolemia is one of the risk factors for colorectal cancer (CRC). Cholesterol can participate in the regulation of human T cell function and affect the occurrence and development of CRC.OBJECTIVE: To elucidate the pathogenesis of CRC immune escape mediated by CD8+ T cell exhaustion induced by cholesterol.
METHODS: CRC samples (n = 217) and healthy individuals (n = 98) were recruited to analyze the relationship between peripheral blood cholesterol levels and the clinical features of CRC. An animal model of CRC with hypercholesterolemia was established. Intraperitoneal intervention with endoplasmic reticulum stress (ERS) inhibitors in hypercholesterolemic CRC mice was performed. CD69, PD1, TIM-3, and CTLA-4 on CD8+ T cells of spleens from C57BL/6 J mice were detected by flow cytometry. CD8+ T cells were cocultured with MC38 cells (mouse colon cancer cell line). The proliferation, apoptosis, migration and invasive ability of MC38 cells were detected by CCK-8 assay, Annexin-V APC/7-AAD double staining, scratch assay and transwell assay, respectively. Transmission electron microscopy was used to observe the ER structure of CD8+ T cells. Western blotting was used to detect the expression of ERS and mitophagy-related proteins. Mitochondrial function and energy metabolism were measured. Immunoprecipitation was used to detect the interaction of endoplasmic reticulum-mitochondria contact site (ERMC) proteins. Immunofluorescence colocalization was used to detect the expression and intracellular localization of ERMC-related molecules.
RESULTS: Peripheral blood cholesterol-related indices, including Tc, low density lipoproteins (LDL) and Apo(a), were all increased, and high density lipoprotein (HDL) was decreased in CRCs. The proliferation, migration and invasion abilities of MC38 cells were enhanced, and the proportion of tumor cell apoptosis was decreased in the high cholesterol group. The expression of IL-2 and TNF-α was decreased, while IFN-γ was increased in the high cholesterol group. It indicated high cholesterol could induce exhaustion of CD8+ T cells, leading to CRC immune escape. Hypercholesterolemia damaged the ER structure of CD8+ T cells and increased the expression of ER stress molecules (CHOP and GRP78), lead to CD8+ T cell exhaustion. The expression of mitophagy-related proteins (BNIP3, PINK and Parkin) in exhausted CD8+ T cells increased at high cholesterol levels, causing mitochondrial energy disturbance. High cholesterol enhanced the colocalization of Fis1/Bap31, MFN2/cox4/HSP90B1, VAPB/PTPIP51, VDAC1/IPR3/GRP75 in ERMCs, indicated that high cholesterol promoted the intermolecular interaction between ER and mitochondrial membranes in CD8+ T cells.
CONCLUSION: High cholesterol regulated the ERS-ERMC-mitophagy axis to induce the exhaustion of CD8+ T cells in CRC.

Keywords: CD8+ T-cell exhaustion; Cholesterol; Colorectal cancer (CRC); ER-mitochondria contact sites (ERMCs); Endoplasmic reticulum stress (ER stress); Mitochondrial energy metabolism

DOI: https://doi.org/10.1007/s00262-023-03555-8

bioRxiv. 2023 Oct 20. pii: 2023.10.18.562926. [Epub ahead of print]

Pathogenic CD8 T cell responses are driven by neutrophil-mediated hypoxia in cutaneous leishmaniasis.

Erin A Fowler, Camila Farias Amorim, Klauss Mostacada, Allison Yan, Laís Amorim Sacramento, Rae A Stanco, Emily D S Hales, Aditi Varkey, Wenjing Zong, Gary D Wu, Camila I de Oliveira, Patrick L Collins, Fernanda O Novais.

Cutaneous leishmaniasis caused by Leishmania parasites exhibits a wide range of clinical manifestations. Although parasites influence disease severity, cytolytic CD8 T cell responses mediate disease. While these responses originate in the lymph node, we find that expression of the cytolytic effector molecule granzyme B is restricted to lesional CD8 T cells in Leishmania -infected mice, suggesting that local cues within inflamed skin induce cytolytic function. Expression of Blimp-1 ( Prdm1 ), a transcription factor necessary for cytolytic CD8 T cell differentiation, is driven by hypoxia within the inflamed skin. Hypoxia is further enhanced by the recruitment of neutrophils that consume oxygen to produce reactive oxygen species, ultimately increasing granzyme B expression in CD8 T cells. Importantly, lesions from cutaneous leishmaniasis patients exhibit hypoxia transcription signatures that correlate with the presence of neutrophils. Thus, targeting hypoxia-driven signals that support local differentiation of cytolytic CD8 T cells may improve the prognosis for patients with cutaneous leishmaniasis, as well as other inflammatory skin diseases where cytolytic CD8 T cells contribute to pathogenesis.

DOI: https://doi.org/10.1101/2023.10.18.562926

Mol Cell Biochem. 2023 Nov 02.

NRF2 signaling pathway and telomere length in aging and age-related diseases.

Alessandro Medoro, Luciano Saso, Giovanni Scapagnini, Sergio Davinelli.

The transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) is well recognized as a critical regulator of redox, metabolic, and protein homeostasis, as well as the regulation of inflammation. An age-associated decline in NRF2 activity may allow oxidative stress to remain unmitigated and affect key features associated with the aging phenotype, including telomere shortening. Telomeres, the protective caps of eukaryotic chromosomes, are highly susceptible to oxidative DNA damage, which can accelerate telomere shortening and, consequently, lead to premature senescence and genomic instability. In this review, we explore how the dysregulation of NRF2, coupled with an increase in oxidative stress, might be a major determinant of telomere shortening and age-related diseases. We discuss the relevance of the connection between NRF2 deficiency in aging and telomere attrition, emphasizing the importance of studying this functional link to enhance our understanding of aging pathologies. Finally, we present a number of compounds that possess the ability to restore NRF2 function, maintain a proper redox balance, and preserve telomere length during aging.

Keywords: Aging; NRF2; Oxidative stress; Telomere length

DOI: https://doi.org/10.1007/s11010-023-04878-x