Activation of TLR4 by viral glycoproteins: A double-edged sword?

Frontiers in Microbiology, Journal Year: 2022, Volume and Issue: 13

Published: Sept. 29, 2022

Recognition of viral infection by pattern recognition receptors is paramount for a successful immune response to infection. However, an unbalanced proinflammatory can be detrimental the host. Recently, multiple studies have identified that SARS-CoV-2 spike protein activates Toll-like receptor 4 (TLR4), resulting in induction cytokine expression. Activation TLR4 glycoproteins has also been observed context other models, including respiratory syncytial virus (RSV), dengue (DENV) and Ebola (EBOV). mechanisms involved virus-TLR4 interactions remained unclear. Here, we review act as pathogen-associated molecular patterns induce via TLR4. We explore current understanding underlying how are recognized discuss contribution activation pathogenesis. identify contentious findings research gaps highlight importance glycoprotein-mediated potential therapeutic approaches.

Language: Английский

---

Regorafenib as a potential drug for severe COVID‐19: inhibition of inflammasome activation in mice

FEBS Open Bio, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 3, 2025

SARS-CoV-2 infection can lead to severe COVID-19, particularly in elderly individuals and those with compromised immunity. Cellular senescence has been implicated as a key pathogenic mechanism. This study investigated the therapeutic potential of regorafenib, previously characterized senomorphic drug, for COVID-19. virus-infected K18-hACE2 mice, overexpressing human ACE2 receptor, exhibited 100% mortality by 10 days post infection. Regorafenib treatment significantly improved survival rates, approximately 43% remaining alive. Mechanistically, regorafenib effectively suppressed type I II interferon cytokine signaling. Notably, inhibited NLR family pyrin domain containing 3 (NLRP3) inflammasome activation, driver storm associated Our findings elucidate molecular mechanisms underlying effects suggest its use promising option

Language: Английский

---

The recombinant spike S1 protein induces injury and inflammation in co-cultures of human alveolar epithelial cells and macrophages

PLoS ONE, Journal Year: 2025, Volume and Issue: 20(2), P. e0318881 - e0318881

Published: Feb. 10, 2025

The current lack of a straightforward and convenient modeling approach to simulate the onset acute lung injury (ALI) has impeded fundamental research hindered screening therapeutic drugs in coronavirus disease 2019 (COVID-19). co-cultured human pulmonary alveolar epithelial cells (HPAEpics) macrophages (AMs) were exposed complete medium, three concentrations recombinant spike S1 protein (0.1, 1, 10 μg/mL), or lipopolysaccharide (LPS) (10 μg/mL). harvested at 2, 3 days post-exposure. Lactate dehydrogenase (LDH) release, IL-6, TNF-ɑ, malondialdehyde (MDA) production quantified compared. Compared those co-cultures HPAEpics AMs concentration μg/mL demonstrated significantly increased levels LDH release (22.9% vs. 9.1%, 25.7%), IL-6 (129 74, 110 pg/mg protein), TNF-ɑ (75 51, 86 protein) production, similar LPS. However, no statistically significant differences observed MDA production. 1 2 post-exposure, post-exposure exhibited (23.4% 14.9%, 16.7%), (127 81, 97 (5.6 3.2, 3.8 nmol/mg but lower (58 79 than After exposure, showed (25.3% 18.4%), (5.5 4.3 compared monocultures, 13.8%), (139 98 4.7 decreased (59 95 monocultures. Conclusions: exposure induced inflammation This methodology for establishing COVID-19-associated ALI model may have promising potential applications value.

Language: Английский

---

The roles of macrophages and monocytes in COVID-19 Severe Respiratory Syndrome

Cell Insight, Journal Year: 2025, Volume and Issue: unknown, P. 100250 - 100250

Published: May 1, 2025

Language: Английский

---

SARS-CoV-2 Spike protein is not pro-inflammatory in human primary macrophages: endotoxin contamination and lack of protein glycosylation as possible confounders

Cell Biology and Toxicology, Journal Year: 2022, Volume and Issue: 38(4), P. 667 - 678

Published: Jan. 11, 2022

The inflammatory potential of SARS-CoV-2 Spike S1 (Spike) has never been tested in human primary macrophages (MΦ). Different recombinant Spikes might display different effects vitro, according to protein length and glycosylation, endotoxin (lipopolysaccharide, LPS) contamination.To assess (1) the on MΦ inflammation; (2) whether LPS contamination is (con)cause vitro increased inflammation.Human were incubated presence/absence several (10 nM) or graded concentrations LPS. Pro-inflammatory marker expression (qPCR ELISA) supernatant (LAL test) main readouts.LPS-free, glycosylated (the form expressed infected humans) caused no inflammation MΦ. Two (out five) contaminated with endotoxins ≥ 3 EU/ml triggered inflammation. A non-contaminated non-glycosylated produced E. coli induced inflammation.Glycosylated per se not pro-inflammatory for MΦ, a feature which may be crucial evade host innate immunity. In studies commercially available should conducted excruciating attention contamination.

Language: Английский

---

Traditional Chinese Medicine, Qingfei Paidu Decoction and Xuanfei Baidu Decoction, Inhibited Cytokine Production via NF-κB Signaling Pathway in Macrophages: Implications for Coronavirus Disease 2019 (COVID-19) Therapy

Frontiers in Pharmacology, Journal Year: 2021, Volume and Issue: 12

Published: Oct. 26, 2021

Background and Aims: Qingfei Paidu decoction (QPD) Xuanfei Baidu (XBD) are two typical traditional Chinese medicines with proven efficacy for the treatment of SARS-CoV-2, although underlying mechanism is not well defined. Blunted immune response enhanced production pro-inflammatory cytokines (cytokine storm) main features observed in patients infected SARS-CoV-2. Analysis based on network pharmacology has revealed that both QPD XBD played an important role regulation host immunity. We therefore investigated modulation innate immunity vitro, focusing type 1 interferon (IFN) signaling pathway A549 cells cytokine macrophages. Methods: were treated or endogenous IFNα IFNβ as expression levels some interferon-stimulated genes (ISGs) detected by reverse transcriptase-quantitative PCR (RT-qPCR). Macrophages derived from THP-1 their measured RT-qPCR, 6 h post LPS stimulation. In addition, further analyzed ELISA. The effect NF-κB pinocytosis activity THP-1-derived macrophages evaluated Western blot neutral red uptake assay, respectively. Results: Although showed very little IFN cells, either markedly inhibited markers including interleukin-6, tumor necrosis factor-α, monocyte chemotactic protein-1, chemokine ligand 10 M1 phosphorylation IκBα p65 during process macrophage polarization was significantly suppressed following treatment. also Conclusion: have been shown to robust anti-inflammatory activities vitro. Our study demonstrated decreased expression, activation pathway, blunted

Language: Английский

---

Diosmectite inhibits the interaction between SARS-CoV-2 and human enterocytes by trapping viral particles, thereby preventing NF-kappaB activation and CXCL10 secretion

Scientific Reports, Journal Year: 2021, Volume and Issue: 11(1)

Published: Nov. 5, 2021

Abstract SARS-CoV-2 enters the intestine by spike protein binding to angiotensin-converting enzyme 2 (ACE2) receptors in enterocyte apical membranes, leading diarrhea some patients. Early treatment of COVID-19-associated could relieve symptoms and limit viral spread within gastrointestinal (GI) tract. Diosmectite, an aluminomagnesium silicate adsorbent clay with antidiarrheal effects, is recommended COVID-19 management protocols. In rotavirus models, diosmectite prevents pathogenic effects virus its enterotoxin. We tested trapping anti-inflammatory properties a model. Trapping were Caco-2 cells using receptor-binding domain (RBD) heat-inactivated preparations. was assessed immunofluorescence, alone or presence cells. The effect on nuclear factor kappa B (NF-kappaB) activation CXCL10 secretion induced RBD analyzed Western blot ELISA, respectively. Diosmectite bound preparation, inhibited interaction ACE2 cell surface. exposure also NF-kappaB secretion. These data provide direct evidence that can bind components inhibit downstream inflammation, supporting mechanistic rationale for consideration as option diarrhea.

Language: Английский

---

Diminazene aceturate inhibits the SARS-CoV-2 spike protein-induced inflammation involving leukocyte migration and DNA extracellular traps formation

Life Sciences, Journal Year: 2024, Volume and Issue: 352, P. 122895 - 122895

Published: July 8, 2024

Language: Английский

---

Inhibitory Effect of Luteolin on Spike S1 Glycoprotein-Induced Inflammation in THP-1 Cells via the ER Stress-Inducing Calcium/CHOP/MAPK Pathway

Pharmaceuticals, Journal Year: 2024, Volume and Issue: 17(10), P. 1402 - 1402

Published: Oct. 20, 2024

The global SARS-CoV-2 outbreak has escalated into a critical public health emergency, with the spike glycoprotein S1 subunit of (spike-S1) linked to inflammation in lung tissue and immune cells. Luteolin, flavone anti-inflammatory properties, shows promise, but research on its effectiveness against long-COVID-related protein-induced responses remains limited. This study aims elucidate underlying mechanisms THP-1 cells induced by spike-S1. Additionally, it seeks assess potential luteolin mitigating inflammatory spike-S1 macrophage model.

Language: Английский

---

Evidence for investigating GSK-3 inhibitors as potential therapeutics for severe COVID-19

Biochemical and Biophysical Research Communications, Journal Year: 2022, Volume and Issue: 605, P. 171 - 176

Published: March 16, 2022

Language: Английский

---