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Characterization of low-density lipoprotein uptake by murine macrophages exposed to Chlamydia pneumoniae
M V Kalayoglu1, G S Miranpuri, D T Golenbock
1Department of Medical Microbiology and Immunology, University of Wisconsin Medical School, 1300 University Avenue, Madison, WI 53706, USA.
Abstract:
Exposure to Chlamydia pneumoniae is correlated with atherosclerosis in a variety of clinical and epidemiological studies, but how the organism may initiate and promote the disease is poorly understood. One pathogenic mechanism could involve modulation of macrophage function by C. pneumoniae. We recently demonstrated that C. pneumoniae induces macrophages to accumulate excess cholesterol and develop into foam cells, the hallmark of early atherosclerotic lesions. To determine if C. pneumoniae-induced foam cell formation involved increased uptake of low-density lipoprotein (LDL), the current study examined macrophage association of a fluorescent carbocyanine (DiI)-labeled LDL following infection. C. pneumoniae enhanced the association of DiI-LDL with macrophages in a dose-dependent manner with respect to both C. pneumoniae and DiI-LDL. Interestingly, increased association was inhibited by native LDL and occurred in the absence of oxidation byproducts and in the presence of antioxidants. However, enhanced DiI-LDL association occurred without the participation of the classical Apo B/E native LDL receptor, since C. pneumoniae increased DiI-LDL association and induced foam cell formation in macrophages isolated from LDL-receptor-deficient mice. Surprisingly, DiI-LDL association was inhibited not only by unlabeled native LDL but also by high-density lipoprotein, very low density lipoprotein, and oxidized LDL. These data indicate that exposure of macrophages to C. pneumoniae increases the uptake of LDL and foam cell formation by an LDL-receptor-independent mechanism.
Insights
Chlamydia pneumoniae infection promotes atherosclerosis by increasing macrophage cholesterol uptake. This occurs via a novel, LDL-receptor-independent pathway, leading to foam cell formation.
Area of Science:
- Infectious diseases
- Cardiovascular research
- Cell biology
Background:
- Chlamydia pneumoniae infection is linked to atherosclerosis.
- The mechanisms by which C. pneumoniae promotes atherosclerosis are not fully understood.
- C. pneumoniae infection induces macrophages to accumulate cholesterol and form foam cells, key features of early atherosclerotic lesions.
Purpose of the Study:
- To investigate whether C. pneumoniae-induced foam cell formation involves increased uptake of low-density lipoprotein (LDL) by macrophages.
- To elucidate the mechanism of enhanced LDL uptake in infected macrophages.
Main Methods:
- Macrophages were infected with C. pneumoniae.
- The association of fluorescently labeled LDL (DiI-LDL) with macrophages was measured.
- Experiments were conducted using LDL-receptor-deficient mice macrophages.
- Inhibition studies were performed using native LDL, HDL, VLDL, and oxidized LDL.
Main Results:
- C. pneumoniae infection dose-dependently enhanced the association of DiI-LDL with macrophages.
- This enhanced association was inhibited by native LDL and occurred independently of LDL oxidation.
- The effect was mediated by an LDL-receptor-independent mechanism, as it occurred in LDL-receptor-deficient macrophages.
- Various lipoproteins, including HDL, VLDL, and oxidized LDL, also inhibited DiI-LDL association.
Conclusions:
- C. pneumoniae infection increases LDL uptake by macrophages through an LDL-receptor-independent pathway.
- This mechanism contributes to foam cell formation and may play a role in the pathogenesis of atherosclerosis.
- The findings reveal a novel mechanism of macrophage lipid accumulation during C. pneumoniae infection.