The role of the immunosuppressive PD-1/PD-L1 checkpoint pathway in the aging process and age-related diseases

Journal of Molecular Medicine, Journal Year: 2024, Volume and Issue: 102(6), P. 733 - 750

Published: April 11, 2024

Abstract The accumulation of senescent cells within tissues is a hallmark the aging process. Senescent are also commonly present in many age-related diseases and cancer microenvironment. escape abnormal from immune surveillance indicates that there some defect function cytotoxic cells, e.g., CD8 + T natural killer (NK) cells. Recent studies have revealed expression programmed death-ligand 1 (PD-L1) protein abundantly increased An increase amount PD-L1 protects clearance by PD-1 checkpoint receptor In fact, activation suppresses properties NK promoting state immunosenescence. inhibitory PD-1/PD-L1 pathway acts cooperation with immunosuppressive cells; for example, can enhance differentiation regulatory (Treg), myeloid-derived suppressor (MDSC), M2 macrophages, whereas cytokines secreted stimulate protein. Interestingly, signaling pathways known to promote cellular senescence process crucial stimulators protein, epigenetic regulation, inflammatory mediators, mTOR-related signaling, cGAS-STING pathway, AhR signaling. It seems axis has role thus it promotes tissues. Thus, blockade might be potential anti-aging senolytic therapy. Key messages accumulate during diseases. able Expression markedly increases Age-related stimulates Inhibitory

Language: Английский

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Emerging diagnostic and therapeutic challenges for skin fibrosis in systemic sclerosis

Molecular Aspects of Medicine, Journal Year: 2024, Volume and Issue: 96, P. 101252 - 101252

Published: Feb. 6, 2024

Systemic sclerosis (also called scleroderma, SSc) is a chronic autoimmune disorder characterized by excessive collagen deposition leading to skin fibrosis and various internal organ manifestations. The emergent diagnostics therapeutic strategies for scleroderma focus on early detection targeted interventions improve patient outcomes quality of life. Diagnostics SSc have evolved significantly in recent years, driven advancements serological markers imaging techniques. Autoantibody profiling, especially antinuclear antibodies (ANA) specific scleroderma-associated autoantibodies, aids identifying subsets predicting disease progression. Furthermore, novel modalities, such as high-frequency ultrasonography optical coherence tomography, enable involvement, enhancing the diagnostic precision allowing tailored management. Therapeutic are multifaceted, targeting immune dysregulation, vascular abnormalities, fibrotic processes. Emerging biologic agents shown promise clinical trials, including monoclonal directed against key cytokines involved fibrosis, transforming growth factor-β (TGF-β) interleukin-6 (IL-6). Additionally, small-molecule inhibitors that disrupt pathways, like tyrosine kinase inhibitors, exhibited potential limiting preventing Stem cell therapy, ablation gene editing techniques hold great regenerating damaged tissue halting Early intervention remains crucial managing SSc, irreversible damage often occurs advanced stages. Novel methods, biomarkers expression being explored identify individuals at high risk developing progressive severe intervene proactively. patient-tailored approaches, employing combination immunosuppressive anti-fibrotic therapies, investigated treatment efficacy while minimizing adverse effects. management this challenging disease. Nevertheless, ongoing research trials needed optimize safety these approaches complex diverse spectrum

Language: Английский

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The role of epithelial cells in fibrosis: Mechanisms and treatment

Pharmacological Research, Journal Year: 2024, Volume and Issue: 202, P. 107144 - 107144

Published: March 13, 2024

Fibrosis is a pathological process that affects multiple organs and considered one of the major causes morbidity mortality in diseases, resulting an enormous disease burden. Current studies have focused on fibroblasts myofibroblasts, which directly lead to imbalance generation degradation extracellular matrix (ECM). In recent years, increasing number role epithelial cells fibrosis. some cases, are first exposed external physicochemical stimuli may drive collagen accumulation mesenchyme. other source stimulation mainly immune cytokines, similarly altered process. this review, we will focus dynamic alterations involved after injury during fibrogenesis, discuss association among them, summarize therapies targeting changed cells. Especially, mesenchymal transition (EMT) key central step, closely linked biological behaviors. Meanwhile, think disruption barrier, cell death basal stem populations stemness fibrosis not appreciated. We believe targeted can prevent progress fibrosis, but reverse it. The provide wonderful preventive delaying action.

Language: Английский

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Bibliometric insights into systemic sclerosis with renal involvement: trends, contributions, and future directions

Renal Failure, Journal Year: 2025, Volume and Issue: 47(1)

Published: Feb. 24, 2025

Background Renal involvement is not uncommon in patients with systemic sclerosis (SSc) and presents various forms, particularly progressing to scleroderma renal crisis (SRC), which associated poor prognosis. Therefore, understanding the research trends this field critical for advancing clinical management therapeutic strategies.

Language: Английский

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Back to the future: targeting the extracellular matrix to treat systemic sclerosis

Nature Reviews Rheumatology, Journal Year: 2023, Volume and Issue: 19(11), P. 713 - 723

Published: Oct. 3, 2023

Language: Английский

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The plasticity of fibroblasts: A forgotten player in the aging process

Ageing Research Reviews, Journal Year: 2023, Volume and Issue: 89, P. 101995 - 101995

Published: June 28, 2023

Tissue-resident fibroblasts are mesenchymal cells which possess an impressive plasticity in their ability to modify properties according the requirements of microenvironment. There diverse subgroups fibroblast phenotypes associated with different tissue pathological conditions, e.g., cancers, wound healing, and many fibrotic inflammatory conditions. The heterogeneous can be subdivided into fibrogenic non-fibrogenic, immunosuppressive subtypes as well cellular senescent subsets. A major hallmark activated is that they contain amounts stress fibers combined α-smooth muscle actin (α-SMA) protein, i.e., commonly this phenotype has been called myofibroblast. Interestingly, several stresses aging process potent inducers myofibroblast differentiation, oxidative endoplasmic reticulum stresses, extracellular matrix (ECM) disorders, mediators, telomere shortening. Accordingly, anti-aging treatments metformin rapamycin inhibited differentiation myofibroblasts tissues. evidence induced cultured does not represent aged Considering versatile frequency structural importance tissues, it seem overlooked players process.

Language: Английский

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Senescent Cells Accumulate in Systemic Sclerosis Skin

Journal of Investigative Dermatology, Journal Year: 2022, Volume and Issue: 143(4), P. 661 - 664.e5

Published: Sept. 30, 2022

Language: Английский

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Further insight into systemic sclerosis from the vasculopathy perspective

Biomedicine & Pharmacotherapy, Journal Year: 2023, Volume and Issue: 166, P. 115282 - 115282

Published: Aug. 9, 2023

Systemic sclerosis (SSc) is an autoimmune disease characterized by immune dysfunction, vascular system and tissue fibrosis. Vascular injury, remodeling, endothelial dysfunction are the hallmark pathological changes of disease. In early stages SSc development, cell injury apoptosis can lead to perivascular inflammation, oxidative stress, hypoxia, which cause clinical manifestations in various organs from skin parenchymal organs. Early diagnosis rational treatment improve patient survival quality life. Ancillary examinations such as nailfold capillaroscopy well optical coherence tomography help detect patients. Studies targeting mechanisms lesions will provide new perspectives for SSc.

Language: Английский

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The contribution of endothelial cells to tissue fibrosis

Current Opinion in Rheumatology, Journal Year: 2023, Volume and Issue: 36(1), P. 52 - 60

Published: Aug. 10, 2023

Purpose of review Tissue fibrosis is an increasingly prevalent condition associated with various diseases and heavily impacting on global morbidity mortality rates. Growing evidence indicates that common cellular molecular mechanisms may drive diverse cause affecting different organs. The scope this to highlight recent findings in support for important role vascular endothelial cells the pathogenesis fibrosis, a special focus systemic sclerosis as prototypic multisystem fibrotic disorder. Recent Although transition fibroblasts chronically activated myofibroblasts widely considered central profibrotic switch, cell involvement development progression has been recognized over last few years. Endothelial can contribute process either directly by acting source through endothelial-to-myofibroblast (EndMT) concomitant microvascular rarefaction, or indirectly becoming senescent and/or secreting variety proinflammatory mediators consequent fibroblast activation recruitment inflammatory/immune further promote fibrosis. Summary An in-depth understanding underlying EndMT acquisition secretory phenotype will provide rationale novel reprogramming-based therapeutic approaches prevent treat

Language: Английский

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Recent Insights into Cellular and Molecular Mechanisms of Defective Angiogenesis in Systemic Sclerosis

Biomedicines, Journal Year: 2024, Volume and Issue: 12(6), P. 1331 - 1331

Published: June 14, 2024

In systemic sclerosis (SSc, or scleroderma), defective angiogenesis, clinically manifesting with abnormal capillary architecture and severe reduction, represents a hallmark of early-stage disease, usually preceding the onset tissue fibrosis, is caused by several cellular molecular mechanisms affecting microvascular endothelial cells different outcomes. Indeed, once damaged, can be dysfunctionally activated, thus becoming unable to undergo angiogenesis promoting perivascular inflammation. They also apoptosis, transdifferentiate into profibrotic myofibroblasts, acquire senescence-associated secretory phenotype characterized release exosomes proinflammatory mediators. this narrative review, we aimed give comprehensive overview recent studies dealing underlying SSc related cell dysfunctions, mainly endothelial-to-mesenchymal transition process. We discussed potential novel vascular treatment strategies able restore angiogenic process reduce in complex disease.

Language: Английский

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