Invariant natural killer T cells: Linking inflammation and neovascularization in human atherosclerosis

Kyriakakis, Emmanouil; Cavallari, Marco; Andert, Jan; Philippova, Maria; Koella, C; Bochkov, Valery N.; Erné, Paul; Wilson, S. Brian; Mori, Lucia; Biedermann, Barbara C.; Resink, Thérèse J.; Libero, Gennaro De

doi:10.1002/eji.201040619

Cited by 57 publications

(48 citation statements)

References 48 publications

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“…In this context, it is tempting to speculate that, under conditions of inflammation, the requirement for a CX3CL1/CX3CR1 migratory axis may have a more pronounced role during trafficking of iNKT cells in the thymus and peripheral compartment. For example, CX3CR1-dependent lymphocyte chemotaxis and iNKT cells have both been implicated in the augmentation of inflammatory diseases such as atherosclerosis (48,49).…”

Section: Discussionmentioning

confidence: 99%

The Thymic Microenvironment Differentially Regulates Development and Trafficking of Invariant NKT Cell Sublineages

Drennan

Govindarajan

Wilde

et al. 2014

The Journal of Immunology

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The regulatory role of the thymic microenvironment during trafficking and differentiation of the invariant NKT (iNKT) cell lineage remains poorly understood. In this study, we show that fractalkine receptor expression marks emigrating subpopulations of the NKT1, NKT2, and NKT17 sublineages in the thymus and peripheral organs of naive mice. Moreover, NKT1 sublineage cells can be subdivided into two subsets, namely NKT1a and NKT1b, which exhibit distinct developmental and tissue-specific distribution profiles. More specifically, development and trafficking of the NKT1a subset are selectively dependent upon lymphotoxin (LT)α1β2-LTβ receptor–dependent differentiation of thymic stroma, whereas the NKT1b, NKT2, and NKT17 sublineages are not. Furthermore, we identify a potential cellular source for LTα1β2 during thymic organogenesis, marked by expression of IL-7Rα, which promotes differentiation of the NKT1a subset in a noncell-autonomous manner. Collectively, we propose a mechanism by which thymic differentiation and retention of the NKT1 sublineage are developmentally coupled to LTα1β2-LTβ receptor–dependent thymic organogenesis.

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Section: Discussionmentioning

confidence: 99%

The Thymic Microenvironment Differentially Regulates Development and Trafficking of Invariant NKT Cell Sublineages

Drennan

Govindarajan

Wilde

et al. 2014

The Journal of Immunology

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“…An underestimated consideration is that iNKT cells can be potent producers of IFN-g by recognizing self lipids in determined situations of danger. It has been proposed that stimulation of these cells complicates lesions and in inflamed atheromas promotes neo-vascularisation [162,163].…”

Section: M2mentioning

confidence: 99%

Are oxidised low-density lipoproteins the true inducers of inflammation in atherosclerosis?

Montero-Vega¹

2014

Inflammasome

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Low-density lipoproteins become oxidised (ox-LDL) when retained in the arterial intima and are considered to be the inducers of inflammation in atherosclerosis. Peroxidation of phospholipids generates a variety of oxidised molecules in LDL and leads to the formation of oxidised lipid-protein adducts. These oxidative modifications are the target of various pattern recognition receptors (PRRs) and constitute immunogenic neoepitopes, termed oxidation-specific epitopes (OSEs). OSEs are thought to be a class of danger-associated molecular patterns (DAMPs) that mediate pro-inflammatory signals in atherosclerosis. Nevertheless, identical OSEs are generated on apoptotic cells that are identified by innate immunity through the same receptors to promote housekeeping tasks and immunosuppression. The present study provides an alternative point of view and proposes that OSEs are ‘waste-associated molecular patterns’ (WAMPs) recognised by innate immunity as a signal for the presence of oxidised waste that must be cleared without triggering inflammation. The hypothesis presented here states that ox-LDL are not inflammatory per se but instead polarise macrophages for housekeeping functions; however, other immune alerts, which are generated under the influence of risk factors, cooperate with them in switching macrophage polarisation towards dangerous phenotypes that complicate atheromas with different tendencies. This hypothesis of ‘immune cooperation’ explains why atheromas grow silently for decades and reveals atherosclerosis to be a dynamic disease that begins with the retention and oxidation of LDL in the arterial intima and ends with the formation of a thrombus, but in which the underlying immune process changes over time and differs between patients.

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“…CD1d is expressed by APCs in mouse and human atherosclerotic lesions [49,50]. Proatherogenic factors such as lysophosphatidic acid and oxidized LDL upregulate the expression of CD1d in DCs [51,52].…”

Section: The Cd1d-inkt Cell Axis In Atherosclerosismentioning

confidence: 99%

The CD1d-Natural Killer T Cell Axis in Atherosclerosis

2013

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A key role for ‘lipid-sensing' CD1-restricted natural killer T (NKT) cells in the pathogenesis of atherosclerosis has been suggested. However, the biology of NKT cells remains poorly characterized, as in different experimental settings their activation was reported to both stimulate and suppress innate and adaptive immune responses. Most of the data from experimental models suggest that NKT cells are proatherogenic; however, it is debated whether the increase in atherosclerosis observed following NKT cell stimulation is a consequence of the inability to induce functional NKT cells rather than the proatherogenic nature of NKT cells. CD1d-expressing antigen-presenting cells and NKT cells were detected in mouse and human atherosclerotic lesions. Furthermore, several lysophospholipids and glycosphingolipids, known to accumulate in atherosclerotic plaques, are antigenic for human NKT cell clones. Lipid transfer proteins, such as apolipoprotein E and microsomal triglyceride transfer protein, are central to NKT cell responses. All these data suggest a profound relation between lipid metabolism, CD1d-NKT cell axis activation and atherosclerosis. In this review, we summarize the advances and gaps in our knowledge of NKT cell biology in the context of atherosclerosis as well as the possibility of influencing NKT cell polarization toward an atheroprotective phenotype.

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Invariant natural killer T cells: Linking inflammation and neovascularization in human atherosclerosis

Cited by 57 publications

References 48 publications

The Thymic Microenvironment Differentially Regulates Development and Trafficking of Invariant NKT Cell Sublineages

The Thymic Microenvironment Differentially Regulates Development and Trafficking of Invariant NKT Cell Sublineages

Are oxidised low-density lipoproteins the true inducers of inflammation in atherosclerosis?

The CD1d-Natural Killer T Cell Axis in Atherosclerosis

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