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  • Review Article
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Inflammation and its resolution in atherosclerosis: mediators and therapeutic opportunities

Nature Reviews Cardiology volume 16, pages 389–406 (2019)Cite this article

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Abstract

Atherosclerosis is a lipid-driven inflammatory disease of the arterial intima in which the balance of pro-inflammatory and inflammation-resolving mechanisms dictates the final clinical outcome. Intimal infiltration and modification of plasma-derived lipoproteins and their uptake mainly by macrophages, with ensuing formation of lipid-filled foam cells, initiate atherosclerotic lesion formation, and deficient efferocytotic removal of apoptotic cells and foam cells sustains lesion progression. Defective efferocytosis, as a sign of inadequate inflammation resolution, leads to accumulation of secondarily necrotic macrophages and foam cells and the formation of an advanced lesion with a necrotic lipid core, indicative of plaque vulnerability. Resolution of inflammation is mediated by specialized pro-resolving lipid mediators derived from omega-3 fatty acids or arachidonic acid and by relevant proteins and signalling gaseous molecules. One of the major effects of inflammation resolution mediators is phenotypic conversion of pro-inflammatory macrophages into macrophages that suppress inflammation and promote healing. In advanced atherosclerotic lesions, the ratio between specialized pro-resolving mediators and pro-inflammatory lipids (in particular leukotrienes) is strikingly low, providing a molecular explanation for the defective inflammation resolution features of these lesions. In this Review, we discuss the mechanisms of the formation of clinically dangerous atherosclerotic lesions and the potential of pro-resolving mediator therapy to inhibit this process.

Key points

  • Modified lipoproteins and cholesterol crystals accumulate in the arterial intima and induce foam cell formation and inflammation.

  • Defective efferocytosis of apoptotic foam cells leads to necrotic core formation.

  • Defective efferocytosis is a sign of failure in the resolution of inflammation.

  • Inflammation resolution is mediated by specialized pro-resolving lipid mediators, proteins and signalling gases.

  • Improvement of the balance between pro-inflammatory and pro-resolving processes enables the resolution of inflammation.

  • Pro-resolving mediator therapy could be a novel approach to suppressing the formation of clinically dangerous atherosclerotic lesions.

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Fig. 1: Ligands and receptors transducing pro-resolving signalling in macrophages.
Fig. 2: Modified lipoproteins and cholesterol crystals induce inflammasome activation.
Fig. 3: Macrophage life cycle and cholesterol round trip in atherosclerosis.
Fig. 4: Defective efferocytosis drives necrotic core formation in atherosclerosis.
Fig. 5: Resolution versus chronic inflammation in atherosclerosis.

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Acknowledgements

M.B.’s research is supported by grants from the Swedish Research Council (2014–2312), the Swedish Heart and Lung Foundation (20180571) and the Marianne and Marcus Wallenberg Foundation (2015.0104). A.Y.’s research is supported by the NIH (T32 HL007343-28 and K99 HL145131). I.T.’s research is supported by the NIH (R01 HL075662, R01 HL127464 and R01 HL132412). K.Ö.’s research is supported by the Academy of Finland (315568), the Aarne Koskelo Foundation and the Finnish Foundation for Cardiovascular Research. The Wihuri Research Institute is maintained by the Jenny and Antti Wihuri Foundation.

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Nature Reviews Cardiology thanks C. J. Binder, K. Ley, and the other anonymous reviewer(s), for their contribution to the peer review of this work.

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  1. Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden

    Magnus Bäck

  2. Columbia University Irving Medical Center, New York, NY, USA

    Arif Yurdagul Jr & Ira Tabas

  3. Atherosclerosis Research Laboratory, Wihuri Research Institute, Helsinki, Finland

    Katariina Öörni & Petri T. Kovanen

  4. Molecular and Integrative Biosciences Research Programme, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland

    Katariina Öörni

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Bäck, M., Yurdagul, A., Tabas, I. et al. Inflammation and its resolution in atherosclerosis: mediators and therapeutic opportunities. Nat Rev Cardiol 16, 389–406 (2019). https://doi.org/10.1038/s41569-019-0169-2

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