Innate immune mechanisms of atherosclerosis
Author: Jiang, Xintong
Date: 2019-06-03
Location: CMM Lecture hall (L8:00), Karolinska University Hospital, Solna
Time: 09.00
Department: Inst för medicin, Solna / Dept of Medicine, Solna
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Thesis (8.028Mb)
Abstract
Atherosclerosis is a multi-factorial immune mediated disease in arterial wall characterized by lipid driven inflammation through activation of the immune system. Chronic vascular inflammation is an important component that modulates atherosclerosis evolution and its complications. The interaction of innate immune activators from both host and environment with innate immune receptors has been considered as one of fundamental mechanisms accounting for the inflammatory responses that affect multiple pathogenic processes during atherosclerosis. The aim of the thesis is to improve our understanding of innate immune mechanisms in atherosclerosis. The objective of the thesis is to investigate the cellular mechanism of NOD1 and TRIM21, to identify the innate immune phenotype of intimal vascular smooth muscle cells (SMC) and to elucidate the activity and clinical relevance of inflammasome-IL-1 signaling in atherosclerosis.
Paper I addresses how the local NOD1 signaling in vascular wall contributes to atherosclerosis and vascular inflammation. We report that a phenotypically distinct subpopulation of VSMC imprinted by NOD1high, a member of NOD-like receptor family, have unique functions in promoting vascular inflammation and lesion development. Paper II reports the identification of a SMC subpopulation with typical innate immune features in human atherosclerosis lesion and rat neointimal lesion. Functional studies and numerical quantifications further establish that these SMCs as important source of arterial resident innate immune effector cells. Paper III investigates inflammasome function and IL-1 generation in human atherosclerosis lesion. IL-1α/β production is a common feature of advanced lesion, and is linked with the regulation of multiple canonical and non-canonical inflammasome. Plaque IL-1β increases in complex plaques and in the patients with hyperlipidemia and no or low-dose statin therapy. Paper IV elucidates the mechanisms of Trim21, an ubiquitin E3 ligase with potent regulatory function in innate immune responses, in the pathogenesis of atherosclerosis. TRIM21 deficiency drives the generation of non-pathogenic Th17 in a cell-intrinsic manner and leads to a more stable plaque phenotype with higher collagen content.
This thesis illustrates the involvement and regulation of different modules in innate immunity in the pathogenesis of atherosclerosis. These notions may provide novel understandings in the inflammatory hypothesis of atherosclerosis and lead to new therapeutic strategies.
Paper I addresses how the local NOD1 signaling in vascular wall contributes to atherosclerosis and vascular inflammation. We report that a phenotypically distinct subpopulation of VSMC imprinted by NOD1high, a member of NOD-like receptor family, have unique functions in promoting vascular inflammation and lesion development. Paper II reports the identification of a SMC subpopulation with typical innate immune features in human atherosclerosis lesion and rat neointimal lesion. Functional studies and numerical quantifications further establish that these SMCs as important source of arterial resident innate immune effector cells. Paper III investigates inflammasome function and IL-1 generation in human atherosclerosis lesion. IL-1α/β production is a common feature of advanced lesion, and is linked with the regulation of multiple canonical and non-canonical inflammasome. Plaque IL-1β increases in complex plaques and in the patients with hyperlipidemia and no or low-dose statin therapy. Paper IV elucidates the mechanisms of Trim21, an ubiquitin E3 ligase with potent regulatory function in innate immune responses, in the pathogenesis of atherosclerosis. TRIM21 deficiency drives the generation of non-pathogenic Th17 in a cell-intrinsic manner and leads to a more stable plaque phenotype with higher collagen content.
This thesis illustrates the involvement and regulation of different modules in innate immunity in the pathogenesis of atherosclerosis. These notions may provide novel understandings in the inflammatory hypothesis of atherosclerosis and lead to new therapeutic strategies.
List of papers:
I. Zhang X, Johansson ME, Jiang X, Ding Y, Gisterå A, Religa P, Hansson GK, Yan ZQ. Implication of NOD1-high smooth muscle cell in vascular inflammation and injury. [Manuscript]
II. Jiang X, Hedin U, Halle M, Hansson GK, Yan ZQ. Evidence for a subtype of human vascular smooth muscle cell as arterial resident innate immune cell. [Manuscript]
III. Jiang X, Wang F, Wang Y, Roy J, Paulsson-Berne G, Hedin U, Lerman A, Hansson GK, Herrmann J, Yan ZQ. Inflammasome-driven interleukin-1α and -1β production in atherosclerotic plaques relates to hyperlipidemia and plaque complexity. [Accepted]
Fulltext (DOI)
Pubmed
IV. Brauner S, Jiang X, Thorlacius GE, Lundberg AM, Östberg T, Yan ZQ, Kuchroo VK, Hansson GK, Wahren-Herlenius M. Augmented Th17 differentiation in Trim21 deficiency promotes a stable phenotype of atherosclerotic plaques with high collagen content. Cardiovasc Res. 2018 Jan 1;114(1):158-167.
Fulltext (DOI)
Pubmed
View record in Web of Science®
I. Zhang X, Johansson ME, Jiang X, Ding Y, Gisterå A, Religa P, Hansson GK, Yan ZQ. Implication of NOD1-high smooth muscle cell in vascular inflammation and injury. [Manuscript]
II. Jiang X, Hedin U, Halle M, Hansson GK, Yan ZQ. Evidence for a subtype of human vascular smooth muscle cell as arterial resident innate immune cell. [Manuscript]
III. Jiang X, Wang F, Wang Y, Roy J, Paulsson-Berne G, Hedin U, Lerman A, Hansson GK, Herrmann J, Yan ZQ. Inflammasome-driven interleukin-1α and -1β production in atherosclerotic plaques relates to hyperlipidemia and plaque complexity. [Accepted]
Fulltext (DOI)
Pubmed
IV. Brauner S, Jiang X, Thorlacius GE, Lundberg AM, Östberg T, Yan ZQ, Kuchroo VK, Hansson GK, Wahren-Herlenius M. Augmented Th17 differentiation in Trim21 deficiency promotes a stable phenotype of atherosclerotic plaques with high collagen content. Cardiovasc Res. 2018 Jan 1;114(1):158-167.
Fulltext (DOI)
Pubmed
View record in Web of Science®
Institution: Karolinska Institutet
Supervisor: Yan, Zhongqun
Co-supervisor: Hansson, Göran K.
Issue date: 2019-05-13
Rights:
Publication year: 2019
ISBN: 978-91-7831-461-4
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