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Excess Inflammasome Activity Leads to Formation of Atherosclerosis

By BiotechDaily International staff writers
Posted on 03 Jul 2018
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Image: Atherosclerotic lesions appear in red in this photomicrograph of a mouse aorta (Photo courtesy of Cedars-Sinai Medical Center).
Image: Atherosclerotic lesions appear in red in this photomicrograph of a mouse aorta (Photo courtesy of Cedars-Sinai Medical Center).
Results presented in a recently published paper explain how chronic inflammation of the arterial walls progresses to arteriosclerosis, a disorder characterized by clogged arteries and increased risk of heart attack and stroke.

Pathogen burden, such as infection by the bacterium Chlamydia pneumoniae (C.pn) accelerates formation of atherosclerosis, but the mechanisms have remained unresolved. As it was known that activation of the NLRP3 inflammasome was linked to atherogenesis, investigators at Cedars-Sinai Medical Center (Los Angeles, CA, USA) examined whether infection stimulated NLRP3 in promoting atherosclerosis.

NALP3 protein, which is encoded by the NLRP3 gene, is expressed predominantly in macrophages and as a component of the inflammasome detects products of damaged cells such as extracellular ATP and crystalline uric acid. Activated NALP3 in turn triggers an immune response. Mutations in the NLRP3 gene are associated with a number of organ specific autoimmune diseases.

The inflammasome is a multiprotein oligomer responsible for the activation of inflammatory responses. It promotes the maturation and secretion of pro-inflammatory cytokines interleukin-1beta (IL-1beta) and interleukin 18 (IL-18). The secretion of these cytokines results in pyroptosis, a form of programmed pro-inflammatory cell death distinct from apoptosis. In the case of dysregulation of the inflammasome, an assortment of major diseases may arise. It is expressed in myeloid cells and is a component of the innate immune system.

For the current study, the investigators worked with cultured human cells and with mice infected by C.pn. Results published in the June 21, 2018, online edition of the journal Cell Metabolism revealed that C.pn potentiated hyperlipidemia-induced inflammasome activity in cultured macrophages and in foam cells in atherosclerotic lesions of mice lacking the LDL (low-density lipoprotein) receptor. C.pn-induced acceleration of atherosclerosis was significantly dependent on NLRP3 and caspase-1.

Mature IL-1beta and cholesterol were found to compete for access to the same transporter for export from macrophages.

"We have known for decades that atherosclerosis is a disease of chronic inflammation that ultimately results in the scarring of arteries and tissue damage," said senior author Dr. Moshe Arditi, professor of pediatrics and biomedical sciences at Cedars-Sinai Medical Center. "But the ongoing stimulus for this inflammation has been unclear. The Cedars-Sinai study raises the possibility that by using drugs to block the initial production of interleukin-1beta, rather than just neutralizing it, a stronger positive effect could be obtained for these patients."

Related Links:
Cedars-Sinai Medical Center


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