Chlamydia pneumoniae Hijacks a Host Autoregulatory IL-1β Loop to Drive Foam Cell Formation and Accelerate Atherosclerosis

Tumurkhuu, Gantsetseg; Dagvadorj, Jargalsaikhan; Porritt, Rebecca A.; Crother, Timothy R.; Shimada, Kenichi; Tarling, Elizabeth J.; Erbay, Ebru; Arditi, Moshe; Chen, Shuang

doi:10.1016/j.cmet.2018.05.027

Cited by 65 publications

(63 citation statements)

References 65 publications

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“…Neuroinflammation is characterized by the release of pro-inflammatory cytokines including interleukin 1b (IL1b), interleukin 6 (IL6) and tumor necrosis factor α (TNFα). These same cytokines are known to increase cholesterol production in peripheral tissues through SREBP2 activation [53][54][55][56] , but their effects on astrocytes have not been tested.…”

Section: Activation Of Astrocytes Cholesterol Synthesis By Inflammatomentioning

confidence: 99%

Regulation of beta-amyloid production in neurons by astrocyte-derived cholesterol

Wang

Kulas

Ferris

et al. 2020

Preprint

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Alzheimer's Disease (AD), a common and burdensome neurodegenerative disorder, is characterized by the presence of β-Amyloid (Aβ) plaques, inflammation, and loss of cognitive function. A cholesteroldependent process sorts Aβ-producing enzymes into nanoscale lipid compartments (also called lipid rafts). Genetic variation in a cholesterol transport protein, apolipoprotein E (apoE), is the most common genetic marker for sporadic AD. Evidence suggests apoE links to Aβ production through lipid rafts, but so far there has been little scientific validation of this link in vivo. Here we use super-resolution imaging to show apoE utilizes astrocyte-derived cholesterol to specifically traffic amyloid precursor protein (APP) into lipid rafts where it interacts with β-and g-secretases to generate Aβ-peptide. We find that targeted deletion of astrocyte cholesterol synthesis robustly reduces amyloid burden in a mouse model of AD. Treatment with cholesterol-free apoE or knockdown of cholesterol synthesis in astrocytes decreases cholesterol levels in cultured neurons and causes APP to traffic out of lipid rafts where it interacts with αsecretase and gives rise to soluble APPα (sAPPα), a neuronal protective product of APP. Changes in cellular cholesterol have no effect on α-, β-, and g-secretase trafficking, suggesting the ratio of Aβ to sAPPα is regulated by the trafficking of the substrate, not the enzymes. Treatment of astrocytes with inflammatory cytokines IL-1β, IL-6 and TNF-α upregulates the synthesis of cholesterol in the astrocytes. We conclude that cholesterol is a signaling molecule kept low in neurons to inhibit raft function, decrease Aβ formation, and enable astrocyte regulation of APP by cholesterol control of substrate presentation. Highlights:ApoE regulates amyloid precursor protein localization to rafts and its exposure to α-vs. β-secretase. α-, β-, and g-Secretases are activated by substrate presentation. ApoE specifically transports astrocyte cholesterol to neurons. Astrocyte cholesterol synthesis disruption prevents Alzheimer's-associated amyloid pathology in mice.

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Section: Activation Of Astrocytes Cholesterol Synthesis By Inflammatomentioning

confidence: 99%

Regulation of beta-amyloid production in neurons by astrocyte-derived cholesterol

Wang

Kulas

Ferris

et al. 2020

Preprint

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“…29 NLRP3-generated IL-1β can significantly increase foam cell formation, downregulate ABCA1, which is a pivotal regulator of cholesterol efflux, in macrophages, and disrupt cholesterol metabolism. 30,31 The liver plays a central role in regulating cholesterol metabolism and it removes cholesterol by converting it to bile salts and eliminating it as bile in feces. 32 The liver contains various proteins involved in the RCT pathway, such as ABCA1 and SR-BI/CLA-1, 33 and ABCA1 expression is regulated by nuclear receptors (NRs).…”

Section: R3 Treatment Affected Cholesterol Transportmentioning

confidence: 99%

Rutaecarpine derivative R3 attenuates atherosclerosis via inhibiting NLRP3 inflammasome‐related inflammation and modulating cholesterol transport

et al. 2019

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Atherosclerosis is a chronic disease characterized by lipid deposition and inflammatory response. NOD‐, LRR‐ and pyrin domain‐containing protein 3 (NLRP3) inflammasome‐facilitated inflammatory responses are crucial in the pathogenesis of atherosclerosis, and thus new therapeutic approaches are emerging that target NLRP3 and inflammation. Here, we explored the anti‐atherosclerotic effect and mechanisms of a new rutaecarpine derivative, 5‐deoxy‐rutaecarpine (R3) in vitro and in vivo. R3 treatment attenuated atherosclerosis development and increased plaque stability in Apoe−/− mice fed a high‐fat diet, and decreased levels of inflammatory mediators, such as interleukin‐1β, in the serum of Apoe−/− mice and in oxidized low‐density lipoprotein (ox‐LDL)‐stimulated murine macrophages. R3 treatment inhibited NLRP3 inflammasome activation in the livers of Apoe−/− mice and ox‐LDL‐stimulated murine macrophages by inhibiting NF‐κB and MAPK pathways. Additionally, R3 significantly decreased total cholesterol in the serum and livers of Apoe−/− mice and promoted cholesterol efflux in murine macrophages through upregulating protein expression of ATP‐binding cassette subfamily A member 1 and scavenger receptor class B type I/human CD36 and lysosomal integral membrane protein‐II analogous‐1. Our results demonstrated that R3 prevented atherosclerotic progression via attenuating NLRP3 inflammasome‐related inflammation and modulating cholesterol transport.

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“…Supporting: Presence of C. pneumoniae in atherosclerotic plaques exacerbates disease pathology; elevated anti-C. pneumoniae antibodies among patients [23][24][25].…”

Section: Atherosclerosismentioning

confidence: 99%

“…Chlamydia facilitates plaque formation by enhancing a firm adhesion of the monocyte to the endothelium [26] and promotes foam cells formation [24]. i.…”

Section: Atherosclerosismentioning

confidence: 99%

Chronic Inflammatory Diseases at Secondary Sites Ensuing Urogenital or Pulmonary Chlamydia Infections

et al. 2020

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Chlamydia trachomatis and C. pneumoniae are members of the Chlamydiaceae family of obligate intracellular bacteria. The former causes diseases predominantly at the mucosal epithelial layer of the urogenital or eye, leading to pelvic inflammatory diseases or blindness; while the latter is a major causative agent for pulmonary infection. On top of these well-described diseases at the respective primary infection sites, Chlamydia are notoriously known to migrate and cause pathologies at remote sites of a host. One such example is the sexually acquired reactive arthritis that often occurs at few weeks after genital C. trachomatis infection. C. pneumoniae, on the other hand, has been implicated in an extensive list of chronic inflammatory diseases which include atherosclerosis, multiple sclerosis, Alzheimer’s disease, asthma, and primary biliary cirrhosis. This review summarizes the Chlamydia infection associated diseases at the secondary sites of infection, and describes the potential mechanisms involved in the disease migration and pathogenesis.

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Chlamydia pneumoniae Hijacks a Host Autoregulatory IL-1β Loop to Drive Foam Cell Formation and Accelerate Atherosclerosis

Cited by 65 publications

References 65 publications

Regulation of beta-amyloid production in neurons by astrocyte-derived cholesterol

Regulation of beta-amyloid production in neurons by astrocyte-derived cholesterol

Rutaecarpine derivative R3 attenuates atherosclerosis via inhibiting NLRP3 inflammasome‐related inflammation and modulating cholesterol transport

Chronic Inflammatory Diseases at Secondary Sites Ensuing Urogenital or Pulmonary Chlamydia Infections

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