HIV Protein Tat Induces Macrophage Dysfunction and Atherosclerosis Development in Low-Density Lipoprotein Receptor–Deficient Mice

Meng, Zhaojie; Hernandez, Rebecca; Liu, Jingwei; Gwag, Taesik; Lu, Weiwei; Hsiai, Tzung K.; Kaul, Marcus; Zhou, Tong; Zhou, Changcheng

doi:10.1007/s10557-021-07141-x

Cited by 9 publications

(18 citation statements)

References 83 publications

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“…C57BL/6J wild-type (WT) mice were purchased from The Jackson Laboratory (Bar Harbor, ME). Myeloid-specific IKKβ knockout (IKKβ ΔMye ) mice on C57BL/6J background (The Jackson Laboratory, Bar Harbor, ME) were generated by crossing mice carrying loxP-flanked IKKβ alleles (IKKβ F/F ) with LysM-Cre transgenic mice, as previously described 21 , 22 . All animals were housed in a pathogen-free environment with a 12 h light-dark cycle under an approved protocol.…”

Section: Methodsmentioning

confidence: 99%

“…Eight-week-old male WT mice were intravenously (IV) injected with 100 µL of Lenti-spike (1.0x10 6 pfu/mL) or control lentivirus followed by IV injection of 100 µL control liposome or Lipo-hACE2 (4 nM) 1 h post infection. On the day of euthanasia, mice were fasted for 6 h following the dark cycle (feeding cycle), and blood and tissues were collected as described previously 19 , 22 .…”

Section: Methodsmentioning

confidence: 99%

“…Peritoneal macrophages were isolated from 8-week-old male IKKβ F/F and IKKβ ΔMye mice as previously described 22 , 23 . Macrophages were seeded to the cell culture plates for 4 h and then treated with Lenti-Spike or control virus for 24 h. Total RNA was extracted, and RNA integrity was confirmed using a dual Agilent 2100 Bioanalyzer (Agilent Technologies Inc., Santa Clara, CA).…”

Section: Methodsmentioning

confidence: 99%

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An engineered nano-liposome-human ACE2 decoy neutralizes SARS-CoV-2 Spike protein-induced inflammation in both murine and human macrophages

et al. 2022

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Rationale: Macrophages are the frontline immune cells in response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Angiotensin-converting enzyme 2 (ACE2) serves as the binding receptor to SARS-CoV-2 Spike glycoprotein for fusion and internalization into the human host cells. However, the mechanisms underlying SARS-CoV-2-elicited macrophage inflammatory responses remain elusive. Neutralizing SARS-CoV-2 by human ACE2 (hACE2) decoys has been proposed as a therapeutic approach to ameliorate SARS-CoV-2-stimulated inflammation. This study aims to investigate whether an engineered decoy receptor can abrogate SARS-CoV-2-induced macrophage inflammation. Methods: hACE2 was biotinylated to the surface of nano-liposomes (d = 100 nm) to generate Liposome-human ACE2 complex (Lipo-hACE2). Lentivirus expressing Spike protein (D614G) was also created as a pseudo-SARS-CoV-2 (Lenti-Spike). Liposome-hACE2 was used as a decoy receptor or competitive inhibitor to inhibit SARS-CoV-2 or Lenti-Spike-induced macrophage inflammation in vitro and in vivo . Results: Both SARS-CoV-2 and Lenti-Spike stimulated strong inflammatory responses by inducing the expression of key cytokine and chemokines, including IL-1β, IL-6, TNFα, CCL-2, and CXCL-10, in murine and human macrophages in vitro , whereas Lipo-hACE2 decoy abolished these effects in macrophages. Furthermore, intravenous injection of Lenti-Spike led to increased macrophage and tissue inflammation in wild type mice, which was also abolished by Lipo-hACE2 treatment. Mechanistically, Spike protein stimulated macrophage inflammation by activating canonical NF-κB signaling. RNA sequencing analysis revealed that Lenti-Spike induced over 2,000 differentially expressed genes (DEGs) in murine macrophages, but deficiency of IκB kinase β (IKKβ), a key regulator for NF-κB activation, abrogated Lenti-Spike-elicited macrophage inflammatory responses. Conclusions: We demonstrated that the engineered Lipo-hACE2 acts as a molecular decoy to neutralize SARS-CoV-2 or Spike protein-induced inflammation in both murine and human macrophages, and activation of the canonical IKKβ/NF-κB signaling is essential for SARS-CoV-2-elicited macrophage inflammatory responses.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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An engineered nano-liposome-human ACE2 decoy neutralizes SARS-CoV-2 Spike protein-induced inflammation in both murine and human macrophages

et al. 2022

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“…Activated NF-κB plays a pivotal role in the formation and stability of atherosclerotic plaques [12]. And in the presence of external risk factors such as high lipid induction, the key step in NF-κB activation is the phosphorylation of IκBα protein.…”

Section: Discussionmentioning

confidence: 99%

NF-κB/ABCA1 Pathway Aggravates ox-LDL-Induced Cell Pyroptosis by Activation of NLRP3 Inflammasomes in THP-1-Derived Macrophages

Li¹,

Liu²,

Yu³

et al. 2021

Preprint

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There is now overwhelming experimental and clinical evidence that atherosclerosis is a chronic inflammatory disease and characterized by lipid deposition in blood vessels. Pyroptosis, an inflammatory form of cell death by certain inflammasomes, has been shown to be associated with the development of AS in recent years. However, the relationship between lipid deposition in foam cells and cell pyroptosis has not been clarified. Here, we demonstrate that with increasing ox-LDL concentration, the expression of pyroptosis associated protein GSDMD, NLRP3 inflammasome gradually increased, intracellular LDH and mature IL-1β release increased, and the proportion of double positive cells with Hoechst/PI staining increased. Interestingly, the expression of NF-κB signal activation marker protein p-NF-κB and p-IκB increased with the increase of ox-LDL concentration. Ox-LDL-induced pyroptosis can be abolished by NF-κB phosphorylation inhibitor, BAY11-7082. Additionally, BAY11-7082 could also significantly up-regulate the protein expression of ABCA1 and eliminate the inhibitory effect of ox-LDL on the expression of ABCA1.Moreover, siABCA1 was transfected into THP-1-derived macrophages under ox-LDL treatment. Compared with the control group, the expression of GSDMD and NLRP3 inflammasome, the release of mature IL-1β and LDH increased, and the proportion of Hoechst/PI staining double-positive cells increased with blocked cholesterol efflux. Finally, cells treated with VX-765, a pyroptosis inhibitor, showed increased cholesterol efflux and cell foaming in THP-1-derived macrophages,which suggest that cell pyroptosis may be a "double-edged sword" in the development of AS. In conclusion,our findings demonstrate for the first time that the NF-κB/ABCA1 pathway is involved in ox-LDL induced pyroptosis by cholesterol efflux blocked activation of NLRP3 inflammasomes in THP-1-derived macrophages, providing a new therapeutic avenue for the prevention and treatment of AS.

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“…IκB kinase (IKK) β is the predominant catalytic subunit of the IKK complex and is required for activation of NF-κB by inflammatory mediators in the canonical or classical activation pathway (9,11,12). We and others have recently revealed the important function of IKKβ in cardiovascular disease and metabolic disorders (11,(13)(14)(15)(16)(17)(18). For example, we found that deficiency of myeloid IKKβ reduced macrophage inflammatory responses and decreased diet-induced atherosclerosis in hyperlipidemic LDL receptor-deficient (LDLR -/-) mice 4 (13).…”

Section: Introductionmentioning

confidence: 99%

Fibroblast-specific IKK-β deficiency ameliorates angiotensin II–induced adverse cardiac remodeling in mice

Lu¹,

Meng²,

Hernandez³

et al. 2021

JCI Insight

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Cardiac inflammation and fibrosis contribute significantly to hypertension-related adverse cardiac remodeling. IκB kinase β (IKK-β), a central coordinator of inflammation through activation of NF-κB, has been demonstrated as a key molecular link between inflammation and cardiovascular disease. However, the cell-specific contribution of IKK-β signaling toward adverse cardiac remodeling remains elusive. Cardiac fibroblasts are one of the most populous nonmyocyte cell types in the heart that play a key role in mediating cardiac fibrosis and remodeling. To investigate the function of fibroblast IKK-β, we generated inducible fibroblast-specific IKK-β–deficient mice. Here, we report an important role of IKK-β in the regulation of fibroblast functions and cardiac remodeling. Fibroblast-specific IKK-β–deficient male mice were protected from angiotensin II–induced cardiac hypertrophy, fibrosis, and macrophage infiltration. Ablation of fibroblast IKK-β inhibited angiotensin II–stimulated fibroblast proinflammatory and profibrogenic responses, leading to ameliorated cardiac remodeling and improved cardiac function in IKK-β–deficient mice. Findings from this study establish fibroblast IKK-β as a key factor regulating cardiac fibrosis and function in hypertension-related cardiac remodeling.

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HIV Protein Tat Induces Macrophage Dysfunction and Atherosclerosis Development in Low-Density Lipoprotein Receptor–Deficient Mice

Cited by 9 publications

References 83 publications

An engineered nano-liposome-human ACE2 decoy neutralizes SARS-CoV-2 Spike protein-induced inflammation in both murine and human macrophages

An engineered nano-liposome-human ACE2 decoy neutralizes SARS-CoV-2 Spike protein-induced inflammation in both murine and human macrophages

NF-κB/ABCA1 Pathway Aggravates ox-LDL-Induced Cell Pyroptosis by Activation of NLRP3 Inflammasomes in THP-1-Derived Macrophages

Fibroblast-specific IKK-β deficiency ameliorates angiotensin II–induced adverse cardiac remodeling in mice

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