Cholesterol-dependent molecular mechanisms contribute to cationic amphiphilic drugs’ prevention of silica-induced inflammation

Kendall, Rebekah L.; Holian, Andrij

doi:10.1016/j.ejcb.2023.151310

Cited by 3 publications

(13 citation statements)

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“…Therefore, the increased 25‐OHC in male airways (Figure 4B) and resulting inhibition of NLRP3/IL‐1β would be protective against macrophage‐mediated MWCNT lung inflammation. Likewise, increased cholesterol content in lysosomal membranes is proposed to be protective against LMP 51,52 . Therefore, lower levels of cholesterol in the lysosomes of female AMs, as mediated by E 2 (Figure 6A), would increase susceptibility to LMP and downstream inflammation.…”

Section: Discussionmentioning

confidence: 99%

“…Likewise, increased cholesterol content in lysosomal membranes is proposed to be protective against LMP. 51,52 Therefore, lower levels of cholesterol in the lysosomes of female AMs, as mediated by E 2 (Figure 6A), would increase susceptibility to LMP and downstream inflammation. Both of these ideas are supported by the greater IL-1β production previously observed in AMs from MWCNT-females.…”

Section: Discussionmentioning

confidence: 99%

“…One pathway by which 25‐OHC can regulate inflammation is by reducing Il1b transcription and NLRP3 inflammasome activation 105 . This pathway is pertinent because the mechanism through which MWCNTs are proposed to cause macrophage death is through a process called lysosomal membrane permeabilization (LMP), whereby once internalized into lysosomes MWCNT interact with the lysosomal membrane in a way that causes pore formation and the release of degradative enzymes into the cytosol, which in turn activates the NLRP3 inflammasome and IL‐1β release 51,106,107 . Therefore, the increased 25‐OHC in male airways (Figure 4B) and resulting inhibition of NLRP3/IL‐1β would be protective against macrophage‐mediated MWCNT lung inflammation.…”

Section: Discussionmentioning

confidence: 99%

“…Bone marrow-derived macrophages (BMDM) were made from male and female WT mice, and age-matched male SR-BI mice, as previously described by our laboratory. 51,52 On BMDM culture day 1, BM cells were collected by flushing the tibia and femur bones with complete media (RPMI, 10% FBS, 1% Penicillin/Streptomycin, 1% Sodium Pyruvate, 0.1% βmercaptoethanol) using a 1/2″ long 27-gauge needle on a 5-10 mL syringe. All BM cells were incubated overnight (37°C; 3.0 × 10 7 cells/20 mL complete media in a T75 flask) to eliminate stromal cells by adherence.…”

Section: Bone Marrow-derived Macrophagesmentioning

confidence: 99%

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Estrogen contributes to sex differences in M2a macrophages during multi‐walled carbon nanotube‐induced respiratory inflammation

Ray,

Postma,

Kendall

et al. 2023

The FASEB Journal

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Lung diseases characterized by type 2 inflammation are reported to occur with a female bias in prevalence/severity in both humans and mice. This includes previous work examining multi‐walled carbon nanotube (MWCNT)‐induced eosinophilic inflammation, in which a more exaggerated M2a phenotype was observed in female alveolar macrophages (AMs) compared to males. The mechanisms responsible for this sex difference in AM phenotype are still unclear, but estrogen receptor (ER) signaling is a likely contributor. Accordingly, male AMs downregulated ERα expression after MWCNT exposure while female AMs did not. Thus, ER antagonist Fulvestrant was administered prior to MWCNT instillation. In females, Fulvestrant significantly attenuated MWCNT‐induced M2a gene expression and eosinophilia without affecting IL‐33. In males, Fulvestrant did not affect eosinophil recruitment but reduced IL‐33 and M2a genes compared to controls. Regulation of cholesterol efflux and oxysterol synthesis is a potential mechanism through which estrogen promotes the M2a phenotype. Levels of oxysterols 25‐OHC and 7α,25‐OHC were higher in the airways of MWCNT‐exposed males compared to MWCNT‐females, which corresponds with the lower IL‐1β production and greater macrophage recruitment previously observed in males. Sex‐based changes in cholesterol efflux transporters Abca1 and Abcg1 were also observed after MWCNT exposure with or without Fulvestrant. In vitro culture with estrogen decreased cellular cholesterol and increased the M2a response in female AMs, but did not affect cholesterol content in male AMs and reduced M2a polarization. These results reveal the modulation of (oxy)sterols as a potential mechanism through which estrogen signaling may regulate AM phenotype resulting in sex differences in downstream respiratory inflammation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Bone Marrow-derived Macrophagesmentioning

confidence: 99%

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Estrogen contributes to sex differences in M2a macrophages during multi‐walled carbon nanotube‐induced respiratory inflammation

Ray,

Postma,

Kendall

et al. 2023

The FASEB Journal

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“…As an inhibitor of aSMase, imipramine is expected to increase lysosomal sphingomyelin and decrease ceramide levels. Previous work by our laboratory indicated that imipramine treatment in bone marrow-derived macrophages increased lysosomal cholesterol levels, which decreased crystalline silica-induced lysosome membrane permeabilization (LMP), subsequent inflammation, and cell death [16]. It was concluded that the imipramine-induced increase in lysosomal cholesterol stabilized the lysosome membrane, preventing LMP and subsequent inflammation.…”

Section: Introductionmentioning

confidence: 96%

Imipramine Treatment Alters Sphingomyelin, Cholesterol, and Glycerophospholipid Metabolism in Isolated Macrophage Lysosomes

Albright,

Sydor,

Shannahan

et al. 2023

Biomolecules

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Lysosomes are degradative organelles that facilitate the removal and recycling of potentially cytotoxic materials and mediate a variety of other cellular processes, such as nutrient sensing, intracellular signaling, and lipid metabolism. Due to these central roles, lysosome dysfunction can lead to deleterious outcomes, including the accumulation of cytotoxic material, inflammation, and cell death. We previously reported that cationic amphiphilic drugs, such as imipramine, alter pH and lipid metabolism within macrophage lysosomes. Therefore, the ability for imipramine to induce changes to the lipid content of isolated macrophage lysosomes was investigated, focusing on sphingomyelin, cholesterol, and glycerophospholipid metabolism as these lipid classes have important roles in inflammation and disease. The lysosomes were isolated from control and imipramine-treated macrophages using density gradient ultracentrifugation, and mass spectrometry was used to measure the changes in their lipid composition. An unsupervised hierarchical cluster analysis revealed a clear differentiation between the imipramine-treated and control lysosomes. There was a significant overall increase in the abundance of specific lipids mostly composed of cholesterol esters, sphingomyelins, and phosphatidylcholines, while lysophosphatidylcholines and ceramides were overall decreased. These results support the conclusion that imipramine’s ability to change the lysosomal pH inhibits multiple pH-sensitive enzymes in macrophage lysosomes.

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Lysosomal BK channels facilitate silica-induced inflammation in macrophages

Kendall,

Holian

2024

Inhalation Toxicology

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Cholesterol-dependent molecular mechanisms contribute to cationic amphiphilic drugs’ prevention of silica-induced inflammation

Cited by 3 publications

References 61 publications

Estrogen contributes to sex differences in M2a macrophages during multi‐walled carbon nanotube‐induced respiratory inflammation

Estrogen contributes to sex differences in M2a macrophages during multi‐walled carbon nanotube‐induced respiratory inflammation

Imipramine Treatment Alters Sphingomyelin, Cholesterol, and Glycerophospholipid Metabolism in Isolated Macrophage Lysosomes

Lysosomal BK channels facilitate silica-induced inflammation in macrophages

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