<i>Chlamydia pneumoniae</i> induces macrophage‐derived foam cell formation via PPAR α and PPAR γ‐dependent pathways

Mei, Chunli; He, Ping; Cheng, Bei; Liu, Wei; Wang, Yan-Fu; Wan, Jingjing

doi:10.1016/j.cellbi.2008.12.002

Cited by 38 publications

(32 citation statements)

References 38 publications

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“…Although PPARγ has been extensively investigated for its role in other diseases (10), its immunoregulatory role(s) in infectious diseases is just now being recognized (46–49). There are two recent reports for altered PPARγ levels during mycobacterial infection in humans, both involving the attenuated BCG.…”

Section: Discussionmentioning

confidence: 99%

Mycobacterium tuberculosis Activates Human Macrophage Peroxisome Proliferator-Activated Receptor γ Linking Mannose Receptor Recognition to Regulation of Immune Responses

Rajaram

Brooks

Morris

et al. 2010

The Journal of Immunology

220

247

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Mycobacterium tuberculosis enhances its survival in macrophages by suppressing immune responses in part through its complex cell wall structures. Peroxisome proliferator-activated receptor γ (PPARγ), a nuclear receptor superfamily member, is a transcriptional factor that regulates inflammation and has high expression in alternatively activated alveolar macrophages and macrophage-derived foam cells, both cell types relevant to tuberculosis pathogenesis. In this study, we show that virulent M. tuberculosis and its cell wall mannose-capped lipoarabinomannan induce PPARγ expression through a macrophage mannose receptor-dependent pathway. When activated, PPARγ promotes IL-8 and cyclooxygenase 2 expression, a process modulated by a PPARγ agonist or antagonist. Upstream, MAPK-p38 mediates cytosolic phospholipase A2 activation, which is required for PPARγ ligand production. The induced IL-8 response mediated by mannose-capped lipoarabinomannan and the mannose receptor is independent of TLR2 and NF-κB activation. In contrast, the attenuated Mycobacterium bovis bacillus Calmette-Guérin induces less PPARγ and preferentially uses the NF-κB–mediated pathway to induce IL-8 production. Finally, PPARγ knockdown in human macrophages enhances TNF production and controls the intracellular growth of M. tuberculosis. These data identify a new molecular pathway that links engagement of the mannose receptor, an important pattern recognition receptor for M. tuberculosis, with PPARγ activation, which regulates the macrophage inflammatory response, thereby playing a role in tuberculosis pathogenesis.

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Section: Discussionmentioning

confidence: 99%

Mycobacterium tuberculosis Activates Human Macrophage Peroxisome Proliferator-Activated Receptor γ Linking Mannose Receptor Recognition to Regulation of Immune Responses

Rajaram

Brooks

Morris

et al. 2010

The Journal of Immunology

220

247

View full text Add to dashboard Cite

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“…The ultrastructural observations provided morphological evidence that C. pneumoniae might not only survive but also develop in macrophages in human atherosclerotic lesions. In accordance with this, in vitro experiments showed that C. pneumoniae infection of monocytes induces their differentiation into macrophages [8,[31][32][33] . The mechanisms by which C. pneumoniae might affect macrophage function have been examined [8,33,36,[70][71][72][73] and it has been also shown that infection of macrophages with C. pneumoniae in vitro accelerates foam cell formation [24,[30][31][32][33][73][74][75][76] .…”

Section: Discussionmentioning

confidence: 50%

“…It has been reported that C. pneumoniae infection accelerates macrophage foam cell formation in vitro through the stimulation of low-density lipoprotein (LDL) oxidization and entry of atherogenic LDL to the cytoplasm, indicating that the microorganism represents a causative agent in atherosclerosis [31][32][33] .…”

Section: Introductionmentioning

confidence: 99%

“…As shown in in vitro studies the infection of arterial cells with C. pneumoniae results in the induction of the expression of inflammatory cytokines, adhesion molecules and matrix metalloproteinases [8,[29][30][31][32][33] . It has been reported that C. pneumoniae infection accelerates macrophage foam cell formation in vitro through the stimulation of low-density lipoprotein (LDL) oxidization and entry of atherogenic LDL to the cytoplasm, indicating that the microorganism represents a causative agent in atherosclerosis [31][32][33] .…”

Section: Introductionmentioning

confidence: 99%

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Decreased Expression of Liver X Receptor-α in Macrophages Infected with <i>Chlamydia pneumoniae</i> in Human Atherosclerotic Arteries in situ

Bobryshev¹,

Orekhov²,

Killingsworth³

et al. 2011

J Innate Immun

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In in vitro experiments, Chlamydia pneumoniae has been shown to infect macrophages and to accelerate foam cell formation. It has been hypothesized that the C. pneumoniae infection affects foam cell formation by suppressing the expression of liver X receptors (LXR), but whether such an event occurs in human atherosclerosis is not known. In this study we examined carotid artery segments, obtained by endarterectomy, in which the presence of C. pneumoniae was confirmed by both polymerase chain reaction and immunohistochemistry. The expression of LXR-α in macrophages infected with C. pneumoniae and macrophages that were not infected was compared using a quantitative immunohistochemical analysis. The analysis revealed a 2.2-fold reduction in the expression of LXR-α in C. pneumoniae-infected cells around the lipid cores in atherosclerotic plaques. In the cytoplasm of laser-capture microdissected cells that were immunopositive for C. pneumoniae, electron microscopy demonstrated the presence of structures with the appearance of elementary, reticulate and aberrant bodies of C. pneumoniae. We conclude that LXR-α expression is reduced in C. pneumoniae-infected macrophages in human atherosclerotic lesions which supports the hypothesis that C. pneumoniae infection might suppress LXR expression in macrophages transforming into foam cells.

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“…The purified mycobacterial cell wall lipoprotein P19 is well-defined as a TLR2 agonist (23). PPARγ is a prime candidate for an intracellular molecular switch based on its central role in controlling the inflammatory response in macrophages (24), and although PPARγ has been extensively investigated in other diseases (25), its immunoregulatory role in infectious diseases (particularly tuberculosis) is just beginning to be recognized (8,26,27). In the present study, the expression of PPARγ in human macrophages was enhanced by M.tb H37Rv and P19, but not M. smegmatis.…”

Section: A B C D Discussionmentioning

confidence: 99%

Mycobacterium tuberculosis 19-kDa lipoprotein induces Toll-like receptor 2-dependent peroxisome proliferator-activated receptor γ expression and promotes inflammatory responses in human macrophages

Liu

Niu

et al. 2014

Molecular Medicine Reports

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Abstract. Mycobacterium tuberculosis (M.tb) enhances its survival in macrophages by suppressing immune responses, in part through its complex cell wall structures. M.tb 19-kDa lipoprotein (P19), a component of the complex cell wall structures of M.tb, is a Toll-like receptor (TLR) agonist, and may induce immune responses through TLR2. Furthermore, the activation of peroxisome proliferator-activated receptor γ (PPARγ) is also involved in M.tb-induced immune responses in macrophages. In the present study, specific agonists/antagonists and siRNA were used to investigate the role of PPARγ in P19-induced immune responses in human macrophages, including TLR2 activation, p38 phosphorylation and cytokine production. In the present study, PPARγ expression, p38 phosphorylation and cytokine production were upregulated following M.tb H37Rv infection or P19 treatment. By pretreating macrophages with a specific PPARγ agonist or antagonist, it was demonstrated that phosphorylation and IL-6 production are modulated in macrophages by PPARγ activity. Following TLR2 knockdown in macrophages, the expression of PPARγ was significantly decreased in the presence or absence of P19 treatment. Furthermore, p38 phosphorylation and cytokine production were significantly reduced in TLR2 knockdown macrophages following P19 treatment. It was demonstrated in the current study that PPARγ was induced and activated by M.tb infection and that P19-induced PPARγ expression, p38 phosphorylation and cytokine production in macrophages are dependent on TLR2. These findings suggest a role for PPARγ and TLR2 in P19-induced p38 phosphorylation and cytokine production, thereby potentially influencing M.tb pathogenesis.

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Chlamydia pneumoniae induces macrophage‐derived foam cell formation via PPAR α and PPAR γ‐dependent pathways

Cited by 38 publications

References 38 publications

Mycobacterium tuberculosis Activates Human Macrophage Peroxisome Proliferator-Activated Receptor γ Linking Mannose Receptor Recognition to Regulation of Immune Responses

Mycobacterium tuberculosis Activates Human Macrophage Peroxisome Proliferator-Activated Receptor γ Linking Mannose Receptor Recognition to Regulation of Immune Responses

Decreased Expression of Liver X Receptor-α in Macrophages Infected with <i>Chlamydia pneumoniae</i> in Human Atherosclerotic Arteries in situ

Mycobacterium tuberculosis 19-kDa lipoprotein induces Toll-like receptor 2-dependent peroxisome proliferator-activated receptor γ expression and promotes inflammatory responses in human macrophages

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