Comprehensive Physiology Wiley Online Library

Innate Immune Cells and Hypertension: Neutrophils and Neutrophil Extracellular Traps (NETs)

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Abstract

Uncontrolled immune system activation amplifies end‐organ injury in hypertension. Nonetheless, the exact mechanisms initiating this exacerbated inflammatory response, thereby contributing to further increases in blood pressure (BP), are still being revealed. While participation of lymphoid‐derived immune cells has been well described in the hypertension literature, the mechanisms by which myeloid‐derived innate immune cells contribute to T cell activation, and subsequent BP elevation, remains an active area of investigation. In this article, we critically analyze the literature to understand how monocytes, macrophages, dendritic cells, and polymorphonuclear leukocytes, including mast cells, eosinophils, basophils, and neutrophils, contribute to hypertension and hypertension‐associated end‐organ injury. The most abundant leukocytes, neutrophils, are indisputably increased in hypertension. However, it is unknown how (and why) they switch from critical first responders of the innate immune system, and homeostatic regulators of BP, to tissue‐damaging, pro‐hypertensive mediators. We propose that myeloperoxidase‐derived pro‐oxidants, neutrophil elastase, neutrophil extracellular traps (NETs), and interactions with other innate and adaptive immune cells are novel mechanisms that could contribute to the inflammatory cascade in hypertension. We further posit that the gut microbiota serves as a set point for neutropoiesis and their function. Finally, given that hypertension appears to be a key risk factor for morbidity and mortality in COVID‐19 patients, we put forth evidence that neutrophils and NETs cause cardiovascular injury post‐coronavirus infection, and thus may be proposed as an intriguing therapeutic target for high‐risk individuals. © 2021 American Physiological Society. Compr Physiol 11:1575‐1589, 2021.

Keywords: immune system; myeloid‐derived immune cells; neutrophils; gut microbiota; blood pressure; oxidative stress; COVID‐19

Figure 1. Figure 1. Myeloid‐derived immune cells that make up the innate immune system include circulating monocytes, tissue‐resident macrophages, antigen‐presenting dendritic cells, and polymorphonuclear leukocytes (also termed granulocytes), such as mast cells, basophils, eosinophils, and neutrophils. Physiologically, these cells co‐exist to maintain homeostasis. For example, acute and controlled activation of these cells dictates an inflammatory milieu that attempts to contain damage, facilitate tissue repair, and direct the adaptive immune system. On the other hand, chronic and uncontrolled activation of these cells can contribute to vascular damage, including endothelial dysfunction, medial thickening, and perivascular adipose tissue inflammation. For example, one of the major functions of activated neutrophils is the expulsion of their DNA as web‐like chromatin structures termed neutrophil extracellular traps (NETs). NETs are a network of extracellular fibers comprising primarily of DNA and citrullinated histone 3 released into the extracellular space in combination with other granule proteins, including neutrophil elastase, myeloperoxidase (MPO), and cathepsin G. This expelled DNA generates a pro‐oxidative, pro‐inflammatory, and pro‐thrombotic milieu capable of inducing endothelial damage. Therefore, NETs are a novel mechanism of vascular injury in hypertension. ROS, reactive oxygen species.
Figure 2. Figure 2. Chemical reactions that make up the respiratory burst function in neutrophils via NADPH oxidase 2 (NOX2). Classically, this is a potent antimicrobial defense against an invading pathogen. Upon endocytosis of the microbe (not depicted), NOX2 produces superoxide (O2−•) from molecular oxygen (O2), and then superoxide is then subsequently converted to other ROS, like hydrogen peroxide (H2O2). In neutrophils, myeloperoxidase (MPO) converts H2O2 to hypohalous acid (HOCl). Based on Singel KL and Segal BH, 2016 194.


Figure 1. Myeloid‐derived immune cells that make up the innate immune system include circulating monocytes, tissue‐resident macrophages, antigen‐presenting dendritic cells, and polymorphonuclear leukocytes (also termed granulocytes), such as mast cells, basophils, eosinophils, and neutrophils. Physiologically, these cells co‐exist to maintain homeostasis. For example, acute and controlled activation of these cells dictates an inflammatory milieu that attempts to contain damage, facilitate tissue repair, and direct the adaptive immune system. On the other hand, chronic and uncontrolled activation of these cells can contribute to vascular damage, including endothelial dysfunction, medial thickening, and perivascular adipose tissue inflammation. For example, one of the major functions of activated neutrophils is the expulsion of their DNA as web‐like chromatin structures termed neutrophil extracellular traps (NETs). NETs are a network of extracellular fibers comprising primarily of DNA and citrullinated histone 3 released into the extracellular space in combination with other granule proteins, including neutrophil elastase, myeloperoxidase (MPO), and cathepsin G. This expelled DNA generates a pro‐oxidative, pro‐inflammatory, and pro‐thrombotic milieu capable of inducing endothelial damage. Therefore, NETs are a novel mechanism of vascular injury in hypertension. ROS, reactive oxygen species.


Figure 2. Chemical reactions that make up the respiratory burst function in neutrophils via NADPH oxidase 2 (NOX2). Classically, this is a potent antimicrobial defense against an invading pathogen. Upon endocytosis of the microbe (not depicted), NOX2 produces superoxide (O2−•) from molecular oxygen (O2), and then superoxide is then subsequently converted to other ROS, like hydrogen peroxide (H2O2). In neutrophils, myeloperoxidase (MPO) converts H2O2 to hypohalous acid (HOCl). Based on Singel KL and Segal BH, 2016 194.
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Cameron G. McCarthy, Piu Saha, Rachel M. Golonka, Camilla F. Wenceslau, Bina Joe, Matam Vijay‐Kumar. Innate Immune Cells and Hypertension: Neutrophils and Neutrophil Extracellular Traps (NETs). Compr Physiol 2021, 11: 1575-1589. doi: 10.1002/cphy.c200020