Immune-mediated mechanisms of atherosclerosis and implications for the clinic.

A large body of evidence supports the inflammatory hypothesis of atherosclerosis, and both innate and adaptive immune responses play important roles in all disease stages. Areas covered: Here, we review our understanding of the role of the immune response in atherosclerosis, focusing on the pathways currently amenable to therapeutic modulation. We also discuss the advantages or undesirable effects that may be foreseen from targeting the immune response in patients at high cardiovascular risk, suggesting new avenues for research. Expert commentary: There is an extraordinary opportunity to directly test the inflammatory hypothesis of atherosclerosis in the clinic using currently available therapeutics. However, a more balanced interpretation of the experimental and translational data is needed, which may help address and identify in more detail the appropriate settings where an immune pathway can be targeted with minimal risk.This is the author accepted manuscript. The final version is available from Taylor & Francis at http://dx.doi.org/10.1080/1744666X.2016.1195686

Regulating heart repair with cardiac-specific T lymphocytes.

Cardiac tissue necrosis secondary to coronary artery occlusion is one of the most common and deadly sterile injuries in developed countries. In this issue of the JCI, Rieckmann et al. identified and characterized antigen-specific CD4+ T helper (Th) cells that developed in the context of myocardial infarction (MI) in mice. They showed that myosin heavy chain α (MYHCA) is a dominant cardiac autoantigen and that T cells with T cell receptor (TCR) specificity to MYHCA acquired a Treg phenotype when adoptively transferred into infarcted mice, which mediated a cardioprotective healing response. Thus, Rieckmann et al. showed that an acute ischemic insult to the heart, which induces sterile inflammation, promoted, rather than limited, protective T cell autoimmunity. Notably, strategies that support an antigen-specific Treg response may limit the immune-inflammatory response and promote cardiac repair after acute MI.This work is supported by the British Heart Foundation (United Kingdom), INSERM (France), and the European Research Council

NLRP3 inflammasome pathways in atherosclerosis.

Atherosclerosis is the major cause of death and disability. Atherosclerotic plaques are characterized by a chronic sterile inflammation in the large blood vessels, where lipid-derived and damage-associated molecular patterns play important roles in inciting immune responses. Following the initial demonstration that NLR family Pyrin domain containing 3 (NLRP3) was important for atherogenesis, a substantial number of studies have emerged addressing the basic mechanisms of inflammasome activation and their relevance to atherosclerosis. In this review, we introduce the basic cellular and molecular mechanisms of NLRP3 inflammasome activation, and discuss the current findings and therapeutic strategies that target NLRP3 inflammasome activation during the development and progression of atherosclerosis

Role of Microvascular Tone and Extracellular Matrix Contraction in the Regulation of Interstitial Fluid: Implications for Aortic Dissection.

The pathophysiology of aortic dissection is poorly understood, and its risk is resistant to medical treatment. Most studies have focused on a proposed pathogenic role of transforming growth factor-β in Marfan disease and related thoracic aortic aneurysms and aortic dissections. However, clinical testing of this concept using angiotensin II type 1 receptor antagonists to block transforming growth factor-β signaling fell short of promise. Genetic mutations that predispose to thoracic aortic aneurysms and aortic dissections affect components of the extracellular matrix and proteins involved in cellular force generation. Thus, a role for dysfunctional mechanosensing in abnormal aortic wall remodeling is emerging. However, how abnormal mechanosensing leads to aortic dissection remains a mystery. Here, we review current knowledge about the regulation of interstitial fluid dynamics and myogenic tone and propose that alteration in contractile force reduces vascular tone in the microcirculation (here, aortic vasa vasorum) and leads to elevations of blood flow, transmural pressure, and fluid flux into the surrounding aortic media. Furthermore, reduced contractile force in medial smooth muscle cells coupled with alteration of structural components of the extracellular matrix limits extracellular matrix contraction, further promoting the formation of intramural edema, a critical step in the initiation of aortic dissection. The concept is supported by several pathophysiological and clinical observations. A direct implication of this concept is that drugs that lower blood pressure and limit interstitial fluid accumulation while preserving or increasing microvascular tone would limit the risk of dissection. In contrast, drugs that substantially lower microvascular tone would be ineffective or may accelerate the disease and precipitate aortic dissection

Commentary: Indoleamine 2,3-Dioxygenase-Expressing Aortic Plasmacytoid Dendritic Cells Protect against Atherosclerosis by Induction of Regulatory T Cells.

No abstract available

Multiple potential roles for B cells in atherosclerosis.

The development of atherosclerosis is the major etiological factor causing cardiovascular disease and constitutes a lipid-induced, chronic inflammatory and autoimmune disease of the large arteries. A long-standing view of the protective role of B cells in atherosclerosis has been challenged by recent studies using B cell depletion in animal models. Whereas complete B cell deficiency increases atherosclerosis, depletion of B2 but not B1 cells reduces atherosclerosis. This has led to a re-evaluation of the multiple potential pathways by which B cells can regulate atherosclerosis, and the apparent opposing roles of B1 and B2 cells. B cells, in addition to having the unique ability to produce antibodies, are now recognized to play a number of important roles in the immune system, including cytokine production and direct regulation of T cell responses. This review summarizes current knowledge on B cell subsets and functions, and how these could distinctly influence atherosclerosis development.This is the author accepted manuscript. The final version is available from Taylor & Francis at http://dx.doi.org/10.3109/07853890.2014.900272

The CXCL10/CXCR3 Axis and Cardiac Inflammation: Implications for Immunotherapy to Treat Infectious and Noninfectious Diseases of the Heart.

Accumulating evidence reveals involvement of T lymphocytes and adaptive immunity in the chronic inflammation associated with infectious and noninfectious diseases of the heart, including coronary artery disease, Kawasaki disease, myocarditis, dilated cardiomyopathies, Chagas, hypertensive left ventricular (LV) hypertrophy, and nonischemic heart failure. Chemokine CXCL10 is elevated in cardiovascular diseases, along with increased cardiac infiltration of proinflammatory Th1 and cytotoxic T cells. CXCL10 is a chemoattractant for these T cells and polarizing factor for the proinflammatory phenotype. Thus, targeting the CXCL10 receptor CXCR3 is a promising therapeutic approach to treating cardiac inflammation. Due to biased signaling CXCR3 also couples to anti-inflammatory signaling and immunosuppressive regulatory T cell formation when activated by CXCL11. Numbers and functionality of regulatory T cells are reduced in patients with cardiac inflammation, supporting the utility of biased agonists or biologicals to simultaneously block the pro-inflammatory and activate the anti-inflammatory actions of CXCR3. Other immunotherapy strategies to boost regulatory T cell actions include intravenous immunoglobulin (IVIG) therapy, adoptive transfer, immunoadsorption, and low-dose interleukin-2/interleukin-2 antibody complexes. Pharmacological approaches include sphingosine 1-phosphate receptor 1 agonists and vitamin D supplementation. A combined strategy of switching CXCR3 signaling from pro- to anti-inflammatory and improving Treg functionality is predicted to synergistically lessen adverse cardiac remodeling

Plan B (-cell) in atherosclerosis.

Atherosclerosis is a leading cause of death worldwide. It is a complex chronic inflammatory disease involving interactions between vascular, circulating and immune cells. B cells play an important role in chronic inflammation producing antibodies and regulating T and natural killer (NKT) cell activation. The role of B cells in atherosclerosis is complex, with atherogenic and protective roles assigned for distinct B cell subsets. Drugs that deplete B cells or modulate their functions are now used in the treatment of various autoimmune diseases in humans. Here, we briefly review the roles of B cell subsets in atherogenesis, and emphasize the potential impact of B cell targeted therapies on the cardiovascular risk of treated patients. Developing more B cell subset-specific therapies would lead to more effective treatments with enhanced safety profile