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Chlamydophila pneumonia phospholipase D is a potent inducer of Th17 inflammation in atherosclerosis

Chlamydophila pneumonia IL-17
Chlamydophila pneumoniae and Th17

Update at BrainImmuneA recent article in PNAS indicates that Chlamydophila pneumoniae phospholipase D (CpPLD) is a major C. pneumoniae factor able to induce Th17 immune response in atherosclerosis.

In 1858, Rudolf Virchow found inflammatory cells in vascular plaques, and, in 1908, Sir William Osler implicated inflammation in the pathogenesis of atherosclerosis. But only research in the recent past has clearly indicated that chronic inflammation is a key factor in atherosclerosis development. Moreover, inflammation also contributes to atherosclerotic plaque disruption and instability, and related unfavourable complications.

The first indication that C. pneumoniae has an association with atherosclerosis and coronary heart disease dates back to 1986. This association has been shown by seroepidemiology, immunohistochemistry, PCR, electron microscopy and tissue culture.

Recent studies implicate T helper 17 (Th17) cells, and the pro-atherogenic role of Th17 cells and their main product, IL-17A, in atherosclerosis. IL-17 has been detected in coronary atherosclerosis, and patients with acute coronary syndrome have increased peripheral Th17 cell number or IL-17 levels. Of note, the concomitant presence of IL-17 and IFN-γ in coronary atherosclerosis, and the presence of IL-17/IFN-γ dual producing T cells within coronary plaques have been reported. Importantly, Th17 cells were also implicated in aortic dissection.

Phospholipases (PLs), a heterogeneous group of proteins with enzymatic activity, able to hydrolize phospholipids, are likely to be involved in membrane disruption occurring in host cell invasion, and bacterial and fungal virulence.

In fact, the realization that some fungal and bacterial toxins were secreted PLs indicated that these molecules were, in fact, virulence factors. One of the most intriguing aspects of phospholipases is their potential to interfere with cellular signaling cascades and to modulate the host–immune response.

In the PNAS study, Marisa Benagiano and colleagues from the Azienda Ospedaliero-Universitaria Careggi Firenze, Florence, Italy characterized the activity of phospholipase D (PLD) as virulence factor in C. pneumoniae infection, we have studied the effect of C. pneumoniae PLD (CpPLD) on the ability of monocytes to prime the innate immune response and the role of CpPLD on endothelial cell (EC) activation.

The authors found that CpPLD-specific T cells were present within the lesion and they exhibited a Th17 cytokine pattern. Moreover, CpPLD-specific T cells were able to strongly promote the production of both tissue factor (TF) and metalloproteinase 9 (MMP-9) involved in plaque rupture and atherotrombotic events.

The authors also demonstrate that CpPLD was able to activate monocytes by binding Toll-like receptor 4 (TLR4), leading to the production of IL-23, IL-6, IL-1β, TGF-β, and CCL-20, molecules critical for the generation, differentiation, and maintenance of Th17 cells.

CpPLD also up-regulated the expression of several chemokines and adhesion molecules such as CXCL-9, CCL-20, CCL-4, CCL-2, ICAM-1, and VCAM-1 in human venular endothelial cells (HUVECs).

All these results demonstrate that CpPLD is able to drive Th17 inflammation within the atherosclerotic plaque. Thus, the study is perhaps the first to suggest that the CpPLD-related Th17 pathway may represent a new therapeutic target for the prevention and/or treatment of atherosclerosis.

Source: Proc Natl Acad Sci U S A, 2012; 109:1222-7. doi: 10.1073/pnas.1111833109. Epub 2012 Jan 9.
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A review in 2014 by Soraya Taleb, Alain Tedgui and Ziad Mallat concluded that the role of IL-17 in cardiovascular disease is context-dependent and may vary according to the cell type producing IL-17 and the cytokine profile of the local microenvironment where IL-17 operates. Enhanced IL-17 production associated with increased IL-10 (regulatory Th17) and reduced IFN-γ will most probably limit lesion development and promote plaque stability. In contrast, dual production of IL-17 and IFN-γ will most likely promote lesion progression and instability.

Chlamydophila pneumonia Th17Figure with the summary of the putative protective and pathogenic effects of IL-17 in atherosclerosis. From: IL-17 and Th17 Cells in Atherosclerosis by S. Taleb, A. Tedgui and Z. Mallat; Arterioscler Thromb Vasc Biol, 2015 Feb;35(2):258-64. Public domain.

IL-6 and transforming growth factor (TGF)-β may induce a subtype of T helper (Th)17 cells that produce both IL-17 and IL-10. Conversely, IL-23 and IL-6 may be involved in the differentiation of pathogenic Th17 cells that produce IL-17 and interferon (IFN)-γ. In addition to Th17 cells, IL-17 can also be produced by other cell types, such as natural killer (NK)T, NK, and γδ T cells. Proatherogenic effects of IL-17 may result from the induction of proinflammatory cytokines (IL-6, granulocyte–macrophage colony-stimulating factor [GM-CSF]) or chemokines (such as CCL2, CXCL1, CXCL8, and CXC10) by endothelial cells, smooth muscle cells (SMC), or macrophages, partly through increased attraction and recruitment of neutrophils and monocytes within the plaques. See more at Arterioscler Thromb Vasc Biol.

A 2017 study demonstrates that healthy elderly-people have an increased Th17 frequency, RORγt expression and Th17 related cytokines (IL-17, IL-6) levels in peripheral blood compared to healthy middle-aged and young-people. Furthermore, elderly-acute cerebral infarction (ACI) patients also have an increased Th17 expression as compared to healthy elderly-people. Thus, Th17 cell response is enhanced with aging and significantly elevated in ACI. Th17/IL-17 can promote endothelial cell senescence and subsequently contribute to ACI occurrence in humans.

A 2018 study indicates that both IL1R and MyD88 signalling in CD4+ T cells promote Th17 immunity, plaque growth and may regulate plaque collagen levels.

Another 2018 study reveals that the Th1, Th9, Th17, Th22, and their transcription factor levels were increased in aortic dissection (AD) patients.

As per R. Saigusa, H. Winkels and K. Ley in a Nat. Rev. Cardiol. 2020 review, T helper 1 (TH1) cells have pro-atherogenic roles and regulatory T (Treg) cells anti-atherogenic roles. The roles in atherosclerosis of other TH cell subsets such as TH2, TH9, TH17, TH22, follicular helper T cells and CD28 T cells, as well as other T cell subsets including CD8+ T cells and γδT cells, are less well understood.

In immune, endothelial and stromal cells, IL-17 induces the secretion of the pro-inflammatory cytokines IL-6, granulocyte-colony stimulating factor) and granulocyte-macrophage colony-stimulating factor, and chemokines, all of which can be pro-atherogenic. By contrast, IL-6 and TGFβ induce a subtype of TH17 cells that produce IL-10 concomitantly with IL-17, and IL-10 can be atheroprotective.

Because of this complexity, experimental studies in Apoe–/– mice on the role of IL-17 have yielded discrepant results: some studies suggest that IL-17A is pro-athrogenic, others atheroprotective and other studies suggest that IL-17 has no effect on atherosclerosis.

Some clinical studies showed that plasma IL-17 levels and the number of peripheral TH17 cells are increased in patients with unstable angina or acute myocardial infarction. However, in larger clinical studies, plasma IL-17 levels were similar in individuals with or without coronary artery disease, and low serum IL-17 levels were associated with a higher risk of cardiovascular events in patients with acute myocardial infarction. In human atherosclerosis, IL-17 is produced concomitantly with IFNγ by T cells infiltrating into coronary artery plaques, and IL-17 and IFNγ synergistically increase pro-inflammatory responses by VSMCs.

A 2020 study demonstrates that Th22 cell-derived IL-22 aggravates atherosclerosis development, in ApoE -/- mice, by enhancing DC-induced Th17 cell proliferation. This is achieved through a mechanism that is associated with IL-6/STAT3 activation, DC-induced Th17 cell proliferation and IL-22-stimulated SMC dedifferentiation into a synthetic phenotype.

Also in 2020, Eliecer Coto et al. determined the relative amount of the Interleukin 17 receptor A (IL17RA) to ACTB transcript in total leukocytes of 55 patients versus 50 healthy controls, all smokers. Patients showed significantly higher mean IL-17RA normalised transcript value than controls, which is in agreement with the putative role for the IL-17 pathway in the pathogenesis of coronary atherosclerosis.