Osteopontin/secreted phosphoprotein‐1 harnesses glial‐, immune‐, and neuronal cell ligand‐receptor interactions to sense and regulate acute and chronic neuroinflammation

Immunological Reviews, Journal Year: 2022, Volume and Issue: 311(1), P. 224 - 233

Published: April 22, 2022

Osteopontin (OPN) also known by its official gene designation secreted phosphoprotein-1 (SPP1) is a fascinating, multifunctional protein expressed in number of cell types that functions not only intercellular communication, but the extracellular matrix (ECM). OPN/SPP1 possesses cytokine, chemokine, and signal transduction virtue modular structural motifs provide interaction surfaces for integrins CD44-variant receptors. In humans, there are three experimentally verified splice variants CD44's ten exons alternatively spiced cell/tissue-specific manner, although very little about how this regulated central nervous system (CNS). Post-translational modifications phosphorylation, glycosylation, localized cleavage specific proteases cells tissues where functions, provides additional layers specificity. However, former make elucidating exact molecular mechanisms function more complex. Flexibility structure engagement with having ability to transmit signals inside-out outside-in direction, likely why can serve as an early detector inflammation ongoing tissue damage response cancer, stroke, traumatic brain injury, pathogenic infection, neurodegeneration, processes impair homeostasis. This review will focus on what currently brain.

Language: Английский

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HIV and cardiovascular disease: the role of inflammation

Current Opinion in HIV and AIDS, Journal Year: 2022, Volume and Issue: 17(5), P. 286 - 292

Published: July 5, 2022

Purpose of review HIV and antiretroviral therapy (ART) use are linked to an increased incidence atherosclerotic cardiovascular disease (ASCVD). Immune activation persists in ART-treated people with (PWH), markers inflammation (i.e. IL-6, C-reactive protein) predict mortality this population. This discusses underlying mechanisms that likely contribute the development ASCVD PWH. Recent findings Persistent contributes accelerated several new insights into immunologic chronic PWH have been made (e.g. clonal haematopoiesis, trained immunity, lipidomics). We will also highlight potential pro-inflammatory may differ vulnerable populations, including women, minorities children. Summary Mechanistic studies drivers ongoing aid tailoring effective therapeutic strategies can reduce risk Focus should include factors lead persistent disparities care comorbidities, sex as a biological factor social determinants health. It remains unclear whether progression is driven by unique mediators (HIV itself, ART, immunodeficiency), or if it version seen general

Language: Английский

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Polyamine metabolism impacts T cell dysfunction in the oral mucosa of people living with HIV

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Jan. 25, 2023

Abstract Metabolic changes in immune cells contribute to both physiological and pathophysiological outcomes of reactions. Here, by comparing protein expression, transcriptome, salivary metabolome profiles uninfected HIV+ individuals, we found perturbations polyamine metabolism the oral mucosa patients. Mechanistic studies using an vitro human tonsil organoid infection model revealed that HIV T also resulted increased synthesis, which was dependent on activities caspase-1, IL-1β, ornithine decarboxylase-1. HIV-1 led a heightened expression synthesis intermediates including decarboxylase-1 as well elevated dysfunctional regulatory cell (T regDys )/T helper 17 (Th17) ratios. Blockade caspase-1 reversed phenotype showing direct role pathway altering functions during infection. Lastly, mucosal /Th17 ratios CD4 hyperactivation positively correlated with putrescine levels, were be saliva Thus, revealing aberrantly infection, our study unveils mechanism chronic viral infections could drive distinct effector programs reg dysfunction.

Language: Английский

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Interleukin 6 Blockade With Tocilizumab Diminishes Indices of Inflammation That Are Linked to Mortality in Treated Human Immunodeficiency Virus Infection

Clinical Infectious Diseases, Journal Year: 2023, Volume and Issue: 77(2), P. 272 - 279

Published: April 3, 2023

Abstract Background People with human immunodeficiency virus (PWH) are at increased risk for comorbidities, and plasma interleukin 6 (IL-6) levels among the most robust predictors of these outcomes. Tocilizumab (TCZ) blocks receptor IL-6, inhibiting functions this cytokine. Methods This was a 40-week, placebo-controlled, crossover trial (NCT02049437) where PWH on stable antiretroviral therapy (ART) were randomized to receive 3 monthly doses TCZ or matching placebo intravenously. Following 10-week treatment period 12-week washout, participants switched opposite treatment. The primary endpoints safety posttreatment C-reactive protein (CRP) CD4+ T-cell cycling. Secondary included changes in inflammatory indices lipid levels. Results There 9 treatment-related toxicities grade 2 greater during administration (mostly neutropenia) administration. Thirty-one 34 completed study modified intent-to-treat analysis. reduced CRP (median decrease, 1819.9 ng/mL, P < .0001; effect size, 0.87) markers PWH, including D-dimer, soluble CD14, tumor necrosis factor receptors. cycling tended decrease all maturation subsets after administration, but only significant naive CD4 T cells. Lipid levels, classes that have been related cardiovascular disease risk, Conclusions is safe decreases inflammation PWH; IL-6 key driver environment predicts morbidity mortality ART-treated PWH. clinical significance elevations requires further study. Clinical Trials Registration. NCT02049437.

Language: Английский

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The kynurenine pathway in HIV, frailty and inflammaging

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: Sept. 8, 2023

Kynurenine (Kyn) is a circulating tryptophan (Trp) catabolite generated by enzymes including IDO1 that are induced inflammatory cytokines such as interferon-gamma. Kyn levels in circulation increase with age and implicated several age-related disorders neurodegeneration, osteoporosis, sarcopenia. Importantly, increases progressive disease HIV patients, antiretroviral therapy does not normalize activity these subjects. now recognized an endogenous agonist of the aryl hydrocarbon receptor, AhR activation itself has been found to induce muscle atrophy, bone-resorbing osteoclasts, decrease matrix formation osteoblasts, lead senescence bone marrow stem cells. Several inhibitors clinical trials potential cancer therapies. We propose some drugs may be repurposed improve musculoskeletal health older adults living HIV.

Language: Английский

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d-Amino acids differentially trigger an inflammatory environment in vitro

Amino Acids, Journal Year: 2024, Volume and Issue: 56(1)

Published: Feb. 3, 2024

Abstract Studies in vivo have demonstrated that the accumulation of d -amino acids ( -AAs) is associated with age-related diseases and increased immune activation. However, underlying mechanism(s) these observations are not well defined. The metabolism -AAs by oxidase (DAO) produces hydrogen peroxide (H 2 O ), a reactive oxygen species involved several physiological processes including response, cell differentiation, proliferation. Excessive levels H contribute to oxidative stress eventual death, characteristic pathology. Here, we explored molecular mechanisms -serine -Ser) -alanine -Ala) human liver cancer cells, HepG2, focus on production downstream secretion pro-inflammatory cytokine chemokine, subsequent death. In HepG2 -Ser decreased induced concentration-dependent depolarization mitochondrial membrane potential (MMP). This was upregulation activated NF-кB, cytokine, TNF-α, IL-8 secretion, apoptosis. Conversely, -Ala-treated cells production, were also accompanied IL-8, but did cause significant present study confirms role both -Ala inducing inflammatory responses, each via unique activation pathways. response apoptotic death only -Ser. Further research required gain better understanding -AA-induced inflammation its consequences, especially context aging given wide detection entities systemic circulation.

Language: Английский

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Monocytes in HIV and SIV Infection and Aging: Implications for Inflamm-Aging and Accelerated Aging

Viruses, Journal Year: 2022, Volume and Issue: 14(2), P. 409 - 409

Published: Feb. 17, 2022

Before the antiretroviral therapy (ART) era, people living with HIV (PLWH) experienced complications due to AIDS more so than aging. With ART and extended lifespan of PLWH, comorbidities also include aging-most likely accelerated aging-as well as a cardiovascular, neurocognitive disorders, lung kidney disease, malignancies. The broad evidence suggests that is associated accentuated aging, age-related occur earlier, in part chronic immune activation, co-infections, possibly effects alone. Normally system undergoes alterations lymphocyte monocyte populations diminished naïve T- B-lymphocyte numbers, reliance on memory lymphocytes, skewed production myeloid cells leading inflammation, termed "inflamm-aging". Specifically, absolute numbers relative proportions monocytes subpopulations are age along mitochondrial dysfunction, resulting increased accumulation reactive oxygen species (ROS). Additionally, an increase biomarkers activation (IL-6, sCD14, sCD163) occurs infection age, may contribute immunosenescence. Chronic accelerates aging; meanwhile, treatment slow acceleration, but not sufficient stop aging or comorbidities. Overall, better understanding mechanisms behind turnover needed for future therapies.

Language: Английский

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Chronic HIV Infection and Aging: Application of a Geroscience-Guided Approach

JAIDS Journal of Acquired Immune Deficiency Syndromes, Journal Year: 2022, Volume and Issue: 89(S1), P. S34 - S46

Published: Jan. 11, 2022

The ability of virally suppressive antiretroviral therapy use to extend the life span people with HIV (PWH) implies that age PWH will also increase. Among PWH, extended survival comes at a cost earlier onset and increased rates aging-associated comorbidities geriatric syndromes, persistent inflammation immune dysregulation consequent chronic infection contributing an overall decrease in health span. geroscience hypothesis proposes root causes most aging-related diseases conditions is aging process itself. Hence, therapeutically targeting fundamental processes could have greater impact on alleviating or delaying than addressing each disease individually. Extending we speculate basic mechanisms improve age. Clinical features pathophysiologic qualitatively resemble those seen older adults without HIV. Therefore, drugs target any pillars aging, including metformin, rapamycin, nicotinamide adenine dinucleotide precursors, may slow rate age-associated syndromes PWH. Drugs selectively induce apoptosis senescent cells, termed senolytics, among Preliminary evidence suggests cell burden implying cells are excellent therapeutic for extending Recently initiated clinical trials evaluating senolytics age-related offer insights into design potential implementation similar

Language: Английский

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Cohort profile: InfCareHIV, a prospective registry-based cohort study of people with diagnosed HIV in Sweden

BMJ Open, Journal Year: 2023, Volume and Issue: 13(3), P. e069688 - e069688

Published: March 1, 2023

The Swedish InfCareHIV cohort was established in 2003 to ensure equal and effective care of people living with HIV (PLHIV) enable long-term follow-up. functions equally as a decision support system quality registry, ensuring up-to-date data reported real time.InfCareHIV includes on >99% all diagnosed Sweden up now 13 029 have been included the cohort. HIV-related biomarkers antiretroviral therapies (ART) also demographics, patient-reported outcome measures experience measures.Sweden 2015 first country reach UNAIDS (United Nations Programme HIV/AIDS)/WHO's 90-90-90 goals. Late diagnosis infection identified key problem HIV-epidemic, low-level viraemia while ART associated all-cause mortality. Increased RNA load cerebrospinal fluid (CSF) despite suppression plasma viral found 5% PLHIV, phenomenon referred 'CSF escape'. Dolutegravir-based treatment PLHIV pre-existing nucleoside reverse transcriptase inhibitor-mutations non-inferior protease inhibitor-based regimens. An increase transmitted drug resistance observed Lower efficacy for inhibitors not due lower adherence treatment. Incidence type 2 diabetes insulin high ageing population. Despite ART, risk infection-related cancer well lung increased compared HIV-negative. were less likely successfully treated cervical precancer more human papillomavirus types current HPV vaccines. Self-reported sexual satisfaction is improving higher women than men.InfCareHIV provides unique base study further improve outcomes, comorbidity management health-related life Sweden.

Language: Английский

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Effects of saponins Rb1 and Re in American ginseng combined intervention on immune system of aging model

Frontiers in Molecular Biosciences, Journal Year: 2024, Volume and Issue: 11

Published: March 28, 2024

Aging is a major risk factor for the development of many pathological processes, such as reduced immunity, cancer, cardiovascular diseases or neurodegenerative diseases, while age-related chronic are most common causes death. This paper studies effects American ginseng saponin Rb 1 and Re alone combined intervention on immune system aging mouse models, by using 30 mg/kg , 15 Re, + (30 (co-intervention) was used to intervene in model, indicators thymus index, spleen interleukin interferon were detected evaluate impact function. The results show that can increase index 7%–12% 12%–19% model. After intervened, apoptotic cells slightly reduced, proportion reduced. combination promote 23.40% 25.5% respectively, which more advantageous than alone. In addition, reduce level INF comparable young mice. not only content, but also TNF content. above delay decline two significantly better individual recovery system. provide theoretical basis data support nutritional supplements its application groups products improve immunity.

Language: Английский

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