The multi-faceted roles of TGF-β in regulation of immunity to infection

Maizels, Rick M.

doi:10.1016/bs.ai.2021.05.001

Cited by 9 publications

(6 citation statements)

References 244 publications

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“…The pathogenesis of SD is still under investigation, but it is already established that a high viral load can lead to extensive cellular activation at the beginning of the infection and subsequent release of high amount of cytokines and chemokines leading to endothelial damage and plasma extravasation 12,30 . Among these proteins, TGF‐β1 has been associated with disease severity and imbalance of the immune response 31 . TGF‐β1 is a pleiotropic cytokine that is produced as a biologically inactive molecule termed latent TGF‐β1 (LTGF‐β) by a broad spectrum of cell types, including dendritic cells, monocytes and macrophages, which are the primary targets of DENV virus 32–35 .…”

Section: Discussionmentioning

confidence: 99%

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Suppression of TGF‐β/Smad2 signaling by GW788388 enhances DENV‐2 clearance in macrophages

et al. 2022

Journal of Medical Virology

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Dengue fever, caused by the dengue virus (DENV-1, −2, −3, and −4), affects millions of people in the tropical and subtropical regions worldwide. Severe dengue is correlated with high viraemia and cytokine storm, such as high levels of transforming growth factor-β1 (TGF-β1) in the patient's serum. Here, the TGF-β1 signaling was investigated in the context of in vitro viral clearance. Macrophages were infected with DENV-2 at MOI 5 and treated with the TGF-β receptor 1 and 2 inhibitor, GW788388. TGF-β1 expression, signal transduction and viral load were evaluated 48 h after DENV-2 infection by enzyme-linked immunoassay, immunofluorescence, and RT-qPCR assays.Total TGF-β1 level was reduced in 15% after DENV-2 infection, but the secretion of its biologically active form increased threefold during infection, which was followed by the phosphorylation of Smad2 protein. Phosphorylation of Smad2 was reduced by treatment with GW788388 and it was correlated with reduced cytokine production.Importantly, treatment led to a dose-dependent reduction in viral load, ranging from 6.6 × 10 5 RNA copies/ml in untreated cultures to 2.3 × 10 3 RNA copies/ml in cultures treated with 2 ng/ml of GW788388. The anti-TGF-β1 antibody treatment also induced a significant reduction in viral load to 1.6 × 10 3 RNA copies/ml. On the other hand, the addition of recombinant TGF-β1 in infected cultures promoted an increase in viral load to 7.0 × 10 6 RNA copies/ml. These results support that TGF-β1 plays a significant role in DENV-2 replication into macrophages and suggest that targeting TGF-β1 may represent an alternative therapeutic strategy to be explored in dengue infection.

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Section: Discussionmentioning

confidence: 99%

“…12,30 Among these proteins, TGF-β1 has been associated with disease severity and imbalance of the immune response. 31 TGF-β1 is a pleiotropic cytokine that is produced as a biologically inactive molecule termed latent TGF-β1…”

Section: Discussionmentioning

confidence: 99%

Suppression of TGF‐β/Smad2 signaling by GW788388 enhances DENV‐2 clearance in macrophages

et al. 2022

Journal of Medical Virology

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“…Thus, TGF-β can impact on a vast number of biologic processes. In the immune system, it is produced by regulatory T cells (Treg), and other cell types, and suppresses or regulates immune responses involving macrophages, dendritic cells, B cells, effector T cells, NK cells and neutrophils ( de Streel and Lucas, 2021 ; Maizels 2021 ; Prud’homme 2007 ). Thus, it is a key regulator of the immune system.…”

Section: Klotho Functions Independent Of Fgf23mentioning

confidence: 99%

Pathobiology of the Klotho Antiaging Protein and Therapeutic Considerations

Prud’homme

Kurt²,

Wang

2022

Front. Aging

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The α-Klotho protein (henceforth denoted Klotho) has antiaging properties, as first observed in mice homozygous for a hypomorphic Klotho gene (kl/kl). These mice have a shortened lifespan, stunted growth, renal disease, hyperphosphatemia, hypercalcemia, vascular calcification, cardiac hypertrophy, hypertension, pulmonary disease, cognitive impairment, multi-organ atrophy and fibrosis. Overexpression of Klotho has opposite effects, extending lifespan. In humans, Klotho levels decline with age, chronic kidney disease, diabetes, Alzheimer’s disease and other conditions. Low Klotho levels correlate with an increase in the death rate from all causes. Klotho acts either as an obligate coreceptor for fibroblast growth factor 23 (FGF23), or as a soluble pleiotropic endocrine hormone (s-Klotho). It is mainly produced in the kidneys, but also in the brain, pancreas and other tissues. On renal tubular-cell membranes, it associates with FGF receptors to bind FGF23. Produced in bones, FGF23 regulates renal excretion of phosphate (phosphaturic effect) and vitamin D metabolism. Lack of Klotho or FGF23 results in hyperphosphatemia and hypervitaminosis D. With age, human renal function often deteriorates, lowering Klotho levels. This appears to promote age-related pathology. Remarkably, Klotho inhibits four pathways that have been linked to aging in various ways: Transforming growth factor β (TGF-β), insulin-like growth factor 1 (IGF-1), Wnt and NF-κB. These can induce cellular senescence, apoptosis, inflammation, immune dysfunction, fibrosis and neoplasia. Furthermore, Klotho increases cell-protective antioxidant enzymes through Nrf2 and FoxO. In accord, preclinical Klotho therapy ameliorated renal, cardiovascular, diabetes-related and neurodegenerative diseases, as well as cancer. s-Klotho protein injection was effective, but requires further investigation. Several drugs enhance circulating Klotho levels, and some cross the blood-brain barrier to potentially act in the brain. In clinical trials, increased Klotho was noted with renin-angiotensin system inhibitors (losartan, valsartan), a statin (fluvastatin), mTOR inhibitors (rapamycin, everolimus), vitamin D and pentoxifylline. In preclinical work, antidiabetic drugs (metformin, GLP-1-based, GABA, PPAR-γ agonists) also enhanced Klotho. Several traditional medicines and/or nutraceuticals increased Klotho in rodents, including astaxanthin, curcumin, ginseng, ligustilide and resveratrol. Notably, exercise and sport activity increased Klotho. This review addresses molecular, physiological and therapeutic aspects of Klotho.

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“…Many infectious agents exploit the pivotal host immunoregulatory pathway driven by transforming growth factor-β (TGF-β) [1,2]. In the case of helminth worm parasites, their fecundity and longevity depends upon a dampened immune system, in some cases muted by regulatory cells induced by cytokines such as TGF-β.…”

Section: Introductionmentioning

confidence: 99%

The helminth TGF-β mimic TGM4 is a modular ligand that binds CD44, CD49d and TGF-β receptors to preferentially target myeloid cells

Singh,

Smyth,

Cunningham

et al. 2023

Preprint

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The murine helminth parasiteHeligmosomoides polygyrusexpresses a family of modular proteins which, replicating the functional activity of the immunomodulatory cytokine TGF-β, have been named TGM (TGF-β Μimic). Multiple domains bind to different receptors, including TGF-β receptors TβRI (ALK5) and TβRII through domains 1-3, and prototypic family member TGM1 binds the cell surface co-receptor CD44 through domains 4-5. This allows TGM1 to induce T lymphocyte Foxp3 expression, characteristic of regulatory (Treg) cells, and to activate a range of TGF-β-responsive cell types. In contrast, a related protein, TGM4, targets a much more restricted cell repertoire, primarily acting on myeloid cells, with less potent effects on T cells and lacking activity on other TGF-β-responsive cell types. TGM4 binds avidly to myeloid cells by flow cytometry, and can outcompete TGM1 for cell binding. Analysis of receptor binding in comparison to TGM1 reveals a 10-fold higher affinity than TGM1 for TGFβR-I (TβRI), but a 100-fold lower affinity for TβRII through Domain 3. Consequently, TGM4 is more dependent on co-receptor binding; in addition to CD44, TGM4 also engages CD49d (Itga4) through Domains 1-3, as well as CD206 and Neuropilin-1 through Domains 4 and 5. TGM4 was found to effectively modulate macrophage populations, inhibiting lipopolysaccharide-driven inflammatory cytokine production and boosting interleukin (IL)-4-stimulated responses such as Arginase-1in vitroandin vivo. These results reveal that the modular nature of TGMs has allowed the fine tuning of the binding affinities of the TβR- and co-receptor binding domains to establish cell specificity for TGF-β signalling in a manner that cannot be attained by the mammalian cytokine.

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The multi-faceted roles of TGF-β in regulation of immunity to infection

Cited by 9 publications

References 244 publications

Suppression of TGF‐β/Smad2 signaling by GW788388 enhances DENV‐2 clearance in macrophages

Suppression of TGF‐β/Smad2 signaling by GW788388 enhances DENV‐2 clearance in macrophages

Pathobiology of the Klotho Antiaging Protein and Therapeutic Considerations

The helminth TGF-β mimic TGM4 is a modular ligand that binds CD44, CD49d and TGF-β receptors to preferentially target myeloid cells

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