Candida albicans Induces Foaming and Inflammation in Macrophages through FABP4: Its Implication for Atherosclerosis

Haider, M.Z.; Al-Rashed, Fatema; Albaqsumi, Zahraa; Alobaid, Khaled; Alqabandi, Rawan; Al-Mulla, Fahd; Ahmad, Rasheed

doi:10.3390/biomedicines9111567

Cited by 10 publications

(7 citation statements)

References 50 publications

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“…Additionally, the phagocytosis of heat-killed Candida albicans by macrophages has been shown to induce foam cell formation and inflammation through upregulation of FABP4 [37]. Although there are few reports of foam cell involvement in aspergillosis, foam cells have been observed in orbital aspergillosis where fine needle aspiration biopsy was performed [38].…”

Section: Discussionmentioning

confidence: 99%

Analysis of chronic host-aspergilloma interactions using a novel mouse model

Hamashima,

Tashiro,

Nakano

et al. 2023

Preprint

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An aspergilloma is a fungus ball caused by chronic infection ofAspergillusspecies in a pre- existing cavity, such as a destroyed lung or the sinuses. Patients with pulmonary aspergilloma are at risk of sudden life-threatening hemoptysis. Antifungal therapy is administered to aspergilloma patients who are ineligible for surgery, but its efficacy is limited. Understanding the pathophysiology of aspergilloma is crucial for developing further treatment strategies. The mechanism behind the long-term host response to aspergilloma is poorly understood. We created a novel mouse model to analyze the host response to aspergilloma by implanting a fungus ball ofAspergillus fumigatusinto an air-filled subcutaneous cavity. Our findings indicate that a live fungus ball led to tissue invasion, even in immunized mice. When a fungus ball consisting of dead hyphae was implanted, it persisted for over three months and induced pathological findings simulating human aspergilloma, including an inflammatory cell infiltration into the fungus ball and angiogenesis in the cavity wall. Dead fungus ball induced Th1 and Th17 inflammatory cytokines and vascular endothelial growth factor. Neutrophils infiltrated the inside of the fungus ball immediately after implantation, and macrophages surrounded it after a one-week delay. The macrophages around the fungus ball were swollen with phagocytosed fragments of dead hyphae and transformed into foam cells containing fat droplets. We also confirmed in vitro that macrophages were damaged and transformed into foam cells by direct contact with dead hyphae. This model holds promise to provide new insights into the fungal-host interaction during aspergillomas.NOTATION OF PRIOR ABSTRACT PUBLICATION/PRESENTATIONNoneIMPORTANCEChronic aspergillosis, which affects over 3 million people worldwide with a 5-year survival rate of 50%, is understudied compared to other forms. Our study focuses on aspergilloma, a key aspect of chronic aspergillosis, using a groundbreaking mouse model that mirrors clinical features over three months. By studying host-fungal interactions within aspergillomas, we discovered Th1 and Th17 inflammatory responses to dead fungal hyphae. Initially, neutrophils dominate, later giving way to macrophages with a lipid-accumulating foamy phenotype. This transition may impede aspergilloma clearance. In addition, even dead hyphae induce vascular endothelial growth factor and promote angiogenesis. Our findings, which are critical for the prevention of fatal hemoptysis, highlight the need for innovative treatments that target fungal clearance and challenge the limited efficacy of antifungal agents against dead fungal bodies. This research represents a significant step forward in the understanding of chronic aspergillosis.

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Section: Discussionmentioning

confidence: 99%

Analysis of chronic host-aspergilloma interactions using a novel mouse model

Hamashima,

Tashiro,

Nakano

et al. 2023

Preprint

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“…2 × 10 4 cells/well were inoculated into 6-well plates. The cells were transfected with 50 nM siCLEC2 using Lipofectamine 2000 in the next day, and siRNA control was also transfected as the siControl group [ 16 ]. The cells were then divided into Control, ox-LDL, ox-LDL+siControl and ox-LDL+siCLEC2 groups.…”

Section: Methodsmentioning

confidence: 99%

Attenuating oxidized low density lipoprotein (ox-LDL)-induced macrophages damage via inhibiting C-type lectin domain family 2 (CLEC2) expression through janus kinase 1 (JAK1)/ signal transducers and activators of transcription-1 (STAT1) pathway

2022

Bioengineered

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Our study aimed to explore the effect of C-type lectin-like receptor 2 (CLEC2) expression level on oxidized low-density lipoprotein (ox-LDL)-induced macrophage damage and the regulatory mechanism of macrophage foaming. Foam cells were derived from RAW264.7 by ox-LDL, and the cell viability was detected by cell counting kit-8 (CCK-8) assay. Enzyme-linked immunosorbent assay (ELISA) was applied to detect the levels of inflammatory cytokines tumor necrosis factor (TNF-α), Interleukin-6 (IL-6), and Interleulin-1β (IL-1β). Small interfering CLEC2 (si-CLEC2) was synthesized and transfected into RAW264.7, and the apoptosis rate was analyzed by flow cytometry. Western blotting was employed to detect the protein expressions of Janus kinase 1 (JAK1), Signal transducers and activators of transcription-1 (STAT1), phosphorylation-JAK1 (p-JAK1), phosphorylation-STAT1 (p-STAT1), CLEC2, and the apoptosis-related proteins. The levels of total cholesterol (TC) and free cholesterol (FC) were measured using colorimetric kits. Results showed that ox-LDL could activate the JAK1/STAT1 pathway of macrophages and up-regulate the expression of CLEC2. CLEC2 knockdown could reduce macrophage inflammation and lipid accumulation. Inactivating JAK1/STAT1 pathway with JAK1 inhibitor can significantly reduce the phosphorylation of STAT1 and alleviate the ox-LDL-induced damage in macrophages by regulating the expression of CLEC2. In conclusion, targeting JAK1/STAT1 to inhibit CLEC2 can attenuate ox-LDL-induced macrophage damage. This study enriched the pathogenesis of atherosclerosis and provided the possible treatment targets.

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“…cDNA synthesis was carried out using 1 µg of the total RNA isolated through the use of a high-capacity cDNA reverse transcription kit (Applied Biosystems, Foster City, CA, USA). 500 ng cDNA was then ampli ed, and the gene expression of (MMP-9, Hs00234579_m1 ; ACSL1, Hs00960561; and GAPDH, Hs03929097_g1) was conducted through the use of TaqMan® Gene Expression Master Mix (Applied Biosystems, Foster City, CA, USA) according to manufacturer's instructions [20][21][22][23] . The threshold cycle (Ct) was normalized to the house-keeping gene GAPDH, and the expression of the target gene was calculated relatively to control using the ΔΔCt-method [24][25][26][27] .…”

Section: Real-time Quantitative Polymerase Chain Reaction (Pcr)mentioning

confidence: 99%

TNFα induces matrix metalloproteinase-9 expression in monocytic cells through ACSL1/JNK/NF- kB signaling pathways

Al-Roub

Akhter

Al-Rashed

et al. 2023

Preprint

Self Cite

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Background Studies have established the association between increased plasma levels of matrix metalloproteinase (MMP)-9 and adipose tissue inflammation. Tumor necrosis factor α (TNFα) was elevated in obesity and is involved in the induction of MMP-9 in monocytic cells. However, the underlying molecular mechanism was incompletely understood. As per our recent report, TNFα mediates inflammatory responses through long-chain acyl-CoA synthetase 1 (ACSL1). Therefore, we further investigated the role of ACSL1 in TNFα-mediated MMP-9 secretion in monocytic cells and macrophages. Methods Monocytic THP-1 cells and macrophages were used to study MMP-9 expression. mRNA and protein levels of MMP-9 were determined by qRT-PCR and ELISA, respectively, and its biological activity was determined by zymography. Signaling pathways were studied using Western blotting, inhibitors, and NF-kB/AP1 reporter cells. Results We found that THP-1 monocytic cells and macrophages displayed increased MMP-9 mRNA expression, as well as biologically active protein secretion after incubation with TNFα. Inhibition of ACSL1 in the cells with triacsin C significantly reduced MMP-9 secretion. However, inhibition of β-oxidation and ceramide biosynthesis was not affected by TNFα-induced MMP-9 production. Using small interfering RNA-mediated knockdown, we further confirmed that TNFα-induced MMP-9 secretion was significantly reduced in ACSL1-deficient cells. Moreover, TNFα-mediated MMP-9 expression was significantly reduced by inhibition of ERK1/ERK2, JNK, and NF-kB signaling pathways. We further observed TNFα-induced phosphorylation of JNK, ERK1/ERK2, and NF-kB. On the other hand, inhibition of ACSL1 reduced TNFα-mediated phosphorylation of JNK, c-Jun, ERK1/2, and NF-kB in THP-1 monocytic cells. In addition, increased NF-κB/AP-1 activity was inhibited in triacsin C-treated cells. Conclusion Altogether, our findings suggest that ACSL1/JNK/ ERK/NF-kB axis plays an important role in the regulation of MMP-9 induced by TNFα in monocytic THP-1 cells and macrophages.

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Candida albicans Induces Foaming and Inflammation in Macrophages through FABP4: Its Implication for Atherosclerosis

Cited by 10 publications

References 50 publications

Analysis of chronic host-aspergilloma interactions using a novel mouse model

Analysis of chronic host-aspergilloma interactions using a novel mouse model

Attenuating oxidized low density lipoprotein (ox-LDL)-induced macrophages damage via inhibiting C-type lectin domain family 2 (CLEC2) expression through janus kinase 1 (JAK1)/ signal transducers and activators of transcription-1 (STAT1) pathway

TNFα induces matrix metalloproteinase-9 expression in monocytic cells through ACSL1/JNK/NF- kB signaling pathways

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