Immune Cells, Inflammation, and Cardiovascular Diseases

Shyam S. Bansal, Shyam S. Bansal

• Verlag: CRC Press
• Jahr: 2022
• ISBN:
  9781000570519
• Auflage: 1
• Thema: Medicina
• Thema: Inmunología

Inflammation, once considered a physiological response to foreign pathogens, is now recognized as a crucial pathological player in the initiation and progression of several chronic diseases, including diabetes, obesity, cancer, Alzheimer's disease, Parkinson's disease, and many others. Considering that cardiovascular diseases are a leading cause of death in the United States and worldwide, the identification of critical inflammatory processes is of utmost importance to devising new immune-based therapeutics that can be added to existing regimens. This book provides detailed information on aspects of inflammation and the manner in which immune activation pathways affect the progression of cardiovascular diseases and the repair/regeneration mechanisms of underlying diseased tissues.

Key Features

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• Outlines the role that inflammation plays in cardiovascular diseases

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• Describes a paradox – neutralization of cytokines that contribute to cardiovascular disease does not show benefit

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• Summarizes research on a variety of processes and mechanisms contributing to cardiovascular pathology

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• Contributions from an international team of leading cardiologists and cardiovascular immunologists

Related Titles

Roy, S., et al., eds. Chronic Inflammation: Molecular Pathophysiology, Nutritional and Therapeutic Interventions (ISBN 978-1-138-19955-2)

Kong, A-N. T., ed. Inflammation, Oxidative Stress, and Cancer: Dietary Approaches for Cancer Prevention (ISBN 978-1-138-19984-2)

Dick, A., et al. Practical Manual of Intraocular Inflammation (ISBN 978-0-367-38720-4)

1 Innate Immune System in Cardiovascular Diseases

Benjamin J. Kopecky and Kory J. Lavine

DOI: 10.1201/b22824-2

CONTENTS

Introduction to Inflammation in Cardiovascular Disease

Innate Immune Cell Heterogeneity

Monocytes

Macrophages

Dendritic Cells

Innate Immune Pathogenesis of Heart Failure

Innate Immune Response to Injury

DAMPs/PAMPs

PRRs

Innate Immune System in Heart Failure Etiologies

Atherosclerosis

Hypertension

Myocardial Ischemia

Myocarditis

Arrhythmias

Cardio-Oncology

Heart Transplant

Conclusion and Future Directions

Bibliography

INTRODUCTION TO INFLAMMATION IN CARDIOVASCULAR DISEASE

The immune system has been implicated in many cardiac disease pathologies, ranging from heart failure to coronary artery disease to myocarditis. In these disease states, markers of systemic inflammation are elevated and are associated with adverse outcomes. However, the cellular sources, mechanisms of activation, and temporal implications of the inflammatory cascade are poorly understood. Early clinical trials broadly targeting inflammation yielded underwhelming results, dampening enthusiasm for further drug development. Recently, there has been renewed interest in the field fueled by new studies identifying surprising heterogeneity within the innate immune cell repertoire. As such, we now understand that diverse populations of innate immune cells reside within the healthy as well as the diseased heart, each with unique origins, dynamics, functions, and potential therapeutic implications.

There are 12 times as many immune cells in the heart compared to skeletal muscle [1]. The immune response is divided into (1) the innate and (2) the humoral/adaptive responses. The innate immune system responds to molecular patterns found in pathogens (pathogen-associated molecular patterns, PAMPs) and to host proteins released following tissue injury (danger-associated molecular patterns, DAMPs). Following activation, innate immune cells express a diverse array of chemokines, cytokines, growth factors, lipid mediators, and oxidative products, with wide-ranging effects on tissue repair, inflammation, and adaptive immunity. During steady state, innate immunity restricts maladaptive activation of the adaptive immune system, but during disease, it activates and targets the adaptive response to the insult. In this chapter, we will focus on the role of the innate immune response and implications for health and cardiovascular disease.

INNATE IMMUNE CELL HETEROGENEITY

The innate immune system has a myriad of cells that can be distinguished by their ontological origin. Hematopoietic stem cells differentiate into common myeloid or lymphoid progenitors. Many innate immune cells originate from the common myeloid progenitor, which subsequently differentiates into the granulocytes (basophils, neutrophils, eosinophils, mast cells), monocytes, and dendritic cell precursors.

During steady-state conditions, granulocytes in the heart are rare. However, following injury, eosinophils, basophils, and mast cells infiltrate the heart. Following myocardial infarction, eosinophils are recruited to the heart in both clinical and experimental models [2, 3]. Genetic depletion of eosinophils in murine models resulted in a reduction of CD206 reparative macrophages (possibly through inter-leukin (IL)-4 signaling) and subsequent adverse remodeling [2, 3], implicating a role for eosinophils conferring protection following myocardial infarction. Opposingly, eosinophils are also associated with heart failure [3]. In a cohort of patients with symptomatic heart failure, Heat2, a long, noncoding RNA, was significantly upregulated [4]. Heat2 is expressed in both eosinophils and basophils and modulates the proliferation, adhesion, invasion, and transmigration of eosinophils and basophils into the heart in the setting of heart failure [4]. Mast cells, another granulocyte, release cytokines (such as tumor necrosis factor (TNF)) that promote myocardial fibrosis and lead to adverse cardiac remodeling after myocardial infarction [5–8]. Genetic depletion of mast cells or mast cell stabilization showed improved outcomes after myocardial injury [9]. Last, neutrophils respond to pro-inflammatory cytokines and chemokines and are recruited to the heart following injury. Heart-resident macrophages can promote recruitment of neutrophils [6]. In summary, the granulocytes are early innate immune response elements that play important roles in the pathogenesis of disease after cardiac injury. They play independent roles as well as integrative roles with other innate immune cells: the monocytes, macrophages, and dendritic cells. We will focus on these three cell populations for the remainder of the chapter.

MONOCYTES

Monocytes are produced in the bone marrow from hematopoietic precursors, most proximally from the common myeloid progenitor [10]. In mice, monocytes can be distinguished on the basis of their expression of Ly6C. Classical monocytes are identified as Ly6c^high CCR2⁺ CX3CR1^low CD62L^high cells [10], while non-classical monocytes are defined as Ly6c^low CCR2⁻ CX3CR1^high CD62L^low cells [11, 12]. Classical (Ly6C^high) monocytes can differentiate into macrophages or non-classical monocytes via Nr4a1 [13, 14]. In humans, classical monocytes are identified as CD14⁺CD16⁻ cells, and nonclassical monocytes are defined as CD16⁺CD14^dim cells [15]. Humans also contain intermediate monocytes (CD14⁺CD16⁺) that harbor functional and phenotypic characteristics of both classical and non-classical monocyte populations. In steady state, mouse monocytes have a life span of 1–2 days, whereas human classical monocytes live for about 3 days [16].

During an inflammatory response, classical monocytes increase in abundance due to expanded myelopoiesis in the bone marrow and spleen through IL-1 signaling [17, 18]. Monocytes extravasate into the bloodstream through a C-C chemokine receptor 2 (CCR2) dependent mechanism [19]. Blood monocytes infiltrate into the heart and differentiate into macrophages or dendritic cell subtypes on the basis of instructive cues derived from the local microenvironment. The role of non-classical monocytes in response to inflammation is poorly understood. However, they are thought to act as intravascular macrophages, patrolling the vascular endothelium to maintain vascular integrity, and may also activate cells with the vascular wall [12].

MACROPHAGES

Specialized macrophages exist in all tissues (liver: Kupfer cells; lung: alveolar macrophages; brain: microglia; bone: osteoclasts; lymph nodes: histiocytes) and play essential roles in embryonic development, homeostasis, disease, and wound healing [20, 21]. Tissue-resident macrophages perform housekeeping and sentinel activities [22–24]. Macrophages engulf pathogens, foreign bodies, and cell debris through phagocytosis to function as antigen-presenting cells to the adaptive...