A New Frontier in Immunometabolism. Cholesterol in Lung Health and Disease

Fessler, Michael B.

doi:10.1513/annalsats.201702-136aw

Cited by 65 publications

(50 citation statements)

References 75 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Systemic cholesterol metabolism in humans influences the lung environment, including the abundance of cholesterol in lung epithelial membranes (Fessler, 2017). Therefore, cholesterol-promoted PDIM spreading may also influence M. tuberculosis transmission.…”

Section: Discussionmentioning

confidence: 99%

Spreading of a mycobacterial cell surface lipid into host epithelial membranes promotes infectivity

Cambier

Banik

Buonomo

et al. 2019

Preprint

View full text Add to dashboard Cite

ABSTRACTSeveral virulence lipids populate the outer cell wall of pathogenic mycobacteria (Jackson, 2014). Phthiocerol dimycocerosate (PDIM), one of the most abundant outer membrane lipids (Anderson, 1929), plays important roles in both defending against host antimicrobial programs (Camacho et al., 2001; Cox et al., 1999; Murry et al., 2009) and in evading these programs altogether (Cambier et al., 2014a; Rousseau et al., 2004). Immediately following infection, mycobacteria rely on PDIM to evade toll-like receptor (TLR)-dependent recruitment of bactericidal monocytes which can clear infection (Cambier et al., 2014b). To circumvent the limitations in using genetics to understand virulence lipid function, we developed a chemical approach to introduce a clickable, semi-synthetic PDIM onto the cell wall of Mycobacterium marinum. Upon infection of zebrafish, we found that PDIM rapidly spreads into host epithelial membranes, and that this spreading inhibits TLR activation. PDIM’s ability to spread into epithelial membranes correlated with its enhanced fluidity afforded by its methyl-branched mycocerosic acids. Additionally, PDIM’s affinity for cholesterol promoted its occupation of epithelial membranes; treatment of zebrafish with statins, cholesterol synthesis inhibitors, decreased spreading and provided protection from infection. This work establishes that interactions between host and pathogen lipids influence mycobacterial infectivity and suggests the use of statins as tuberculosis preventive therapy by inhibiting PDIM spread.

show abstract

Section: Discussionmentioning

confidence: 99%

Spreading of a mycobacterial cell surface lipid into host epithelial membranes promotes infectivity

Cambier

Banik

Buonomo

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…The TF Srebf2, also known as Srebp2, was increasing its connectivity over time in the CNT subnetworks for high doses of these agents. Srebf2 induces the expression genes that are involved in cholesterol and fatty acid synthesis, cholesterol transport [46,47] and in the formation of lipid-laden macrophages (foam cell) [48], which are associated with lung fibrosis [49]. Surprisingly, TFs from the cell cycle and DNA damage module, which included dozens of upregulated genes in all networks (as mentioned above), were weakly represented in the CNTs subnetworks.…”

Section: Analysis Of Gene Regulatorsmentioning

confidence: 96%

Transcriptional regulatory mechanisms of fibrosis development in mouse lung tissue exposed to carbon nanotubes

Zhernovkov

Santra

Cassidy

et al. 2018

Preprint

View full text Add to dashboard Cite

BackgroundCarbon nanotubes (CNTs) usage has rapidly increased in the last few decades due to their unique properties, exploited in various industrial and commercial products. Certain types of CNTs cause adverse health effects, including chronic inflammation and fibrosis. Despite the large number of in vitro and in vivo studies evaluating these effects, many important questions remain unanswered due to a lack of mechanistic understanding of how CNTs induce cellular stress responses. In order to predict CNT toxicity, it is important to understand which transcriptional programs are specifically activated in response to CNTs, and what similarities and differences exist in relation to other toxic inducers exerting similar adverse effects. ResultsA systems biology approach was applied to reveal complex interactions at the molecular level in mouse lung tissue in response to different fibrosis inducers: two types of multiwalled CNTs, NM-401 and NRCWE-26, and bleomycin (BLM). Based on mRNA gene expression profiles, we inferred gene regulatory networks (GRNs) to capture functional hierarchical regulatory structures between genes and their regulators. We found that activities of the transcription factors (TFs) Myc, Arid5a and Mxd1 were associated with the regulation of cytokine transcription in response to CNTs, while in response to BLM treatment, Myc was associated with p53 signaling. TF Litaf was identified as the essential regulator for noncanonical signaling of TLR2/4 driven by CNTs. Despite the different nature of the lung injury caused by CNTs and BLM, we identified common stress response modules, that included DNA damage (TFs : E2f8, E2f1, Foxm1), M1/M2 macrophage polarization (TF: Mafb), Interferon response (TFs: Irf7, Stat2 and Irf9) for all agents. ConclusionsThese results suggest that the reconstruction and analysis of TF-centric gene interaction networks can reveal key targets and regulators of cellular stress responses to toxic agents.2

show abstract

“…The connectivity of Srebf2, also known as Srebp2, rose as the NM-401 dose increased. Srebf2 induces the expression of genes that are involved in cholesterol and fatty acid synthesis, cholesterol transport (Fessler, 2017;Madison, 2016), and the formation of lipid-laden macrophages (foam cells) (Li et al, 2013), which are associated with lung fibrosis (Romero et al, 2015). Thrb regulates biological functions of thyroid hormone, which can be involved in induction of oxidative stress and inflammation (Mancini et al, 2016).…”

Section: Prioritization Of Gene Regulators Of Fibrosismentioning

confidence: 99%

An Integrative Computational Approach for a Prioritization of Key Transcription Regulators Associated With Nanomaterial-Induced Toxicity

Zhernovkov¹,

Santra²,

Cassidy³

et al. 2019

Toxicological Sciences

View full text Add to dashboard Cite

A rapid increase of new nanomaterial (NM) products poses new challenges for their risk assessment. Current traditional methods for estimating potential adverse health effect of NMs are complex, time consuming, and expensive. In order to develop new prediction tests for nanotoxicity evaluation, a systems biology approach, and data from high-throughput omics experiments can be used. We present a computational approach that combines reverse engineering techniques, network analysis and pathway enrichment analysis for inferring the transcriptional regulation landscape and its functional interpretation. To illustrate this approach, we used published transcriptomic data derived from mice lung tissue exposed to carbon nanotubes (NM-401 and NRCWE-26). Because fibrosis is the most common adverse effect of these NMs, we included in our analysis the data for bleomycin (BLM) treatment, which is a well-known fibrosis inducer. We inferred gene regulatory networks for each NM and BLM to capture functional hierarchical regulatory structures between genes and their regulators. Despite the different nature of the lung injury caused by nanoparticles and BLM, we identified several conserved core regulators for all agents. We reason that these regulators can be considered as early predictors of toxic responses after NMs exposure. This integrative approach, which refines traditional methods of transcriptomic analysis, can be useful for prioritization of potential core regulators and generation of new hypothesis about mechanisms of nanoparticles toxicity.

show abstract

A New Frontier in Immunometabolism. Cholesterol in Lung Health and Disease

Cited by 65 publications

References 75 publications

Spreading of a mycobacterial cell surface lipid into host epithelial membranes promotes infectivity

Spreading of a mycobacterial cell surface lipid into host epithelial membranes promotes infectivity

Transcriptional regulatory mechanisms of fibrosis development in mouse lung tissue exposed to carbon nanotubes

An Integrative Computational Approach for a Prioritization of Key Transcription Regulators Associated With Nanomaterial-Induced Toxicity

Contact Info

Product

Resources

About