Trained Innate Immunity in Animal Models of Cardiovascular Diseases

Abstract

Acquisition of immunological memory is an important evolutionary strategy that evolved to protect the host from repetitive challenges from infectious agents. It was believed for a long time that memory formation exclusively occurs in the adaptive part of the immune system with the formation of highly specific memory T cells and B cells. In the past 10-15 years, it has become clear that innate immune cells, such as monocytes, natural killer cells, or neutrophil granulocytes, also have the ability to generate some kind of memory. After the exposure of innate immune cells to certain stimuli, these cells develop an enhanced secondary response with increased cytokine secretion even after an encounter with an unrelated stimulus. This phenomenon has been termed trained innate immunity (TI) and is associated with epigenetic modifications (histone methylation, acetylation) and metabolic alterations (elevated glycolysis, lactate production). TI has been observed in tissue-resident or circulating immune cells but also in bone marrow progenitors. Risk-factors for cardiovascular diseases (CVDs) which are associated with low-grade inflammation, such as hyperglycemia, obesity, or high salt, can also induce TI with a profound impact on the development and progression of CVDs. In this review, we briefly describe basic mechanisms of TI and summarize animal studies which specifically focus on TI in the context of CVDs.

Keywords: animal models; bone marrow; cardiovascular diseases; monocytes; trained innate immunity.

Figure 1

Stimuli and effects of innate immune training: Primary stimulation (1st stimulus) of innate immune cells (e.g., monocytes) by pathogen-derived or endogenous molecules leads to a transient immune response with elevated cytokine expression but can also induce metabolic and epigenetic adaptations that can be maintained over weeks or months. Stimulation of these cells a second time, even with an unrelated stimulus (this can occur after days, weeks or several months), results in an aggravated secondary response with enhanced release of inflammatory cytokines, chemokines, or reactive oxygen species. This can support the fight against infectious pathogens but can also lead to severe tissue destruction, in the context of autoimmune or autoinflammatory diseases. The curve in the lower part of the figure displays a schematic representation of an immune response of isolated monocytes stimulated in vitro with oxLDL (oxidized low-density lipoprotein) or β-glucan followed by a second stimulation (e.g., with lipopolysaccharide (LPS)) after one week. The x-axis displays the time (in days), and the y-axis represents the magnitude of the innate immune response. As shown by in vivo animal studies and ex vivo experiments with isolated cells from humans, an enhanced secondary response can also be found weeks or months after the first stimulus. Parts of the figure were drawn using pictures from Servier Medical Art. Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License (https://creativecommons.org/licenses/by/3.0/ (accessed on 7 January 2024)). (BCG = Bacille Calmette–Guérin; HBV = hepatitis B Virus; MMPs = matrix metalloproteinases).

Figure 2

Schematic overview of the interactions between trained innate immunity and cardiovascular diseases. Various innate immune cell types including stem and progenitor cells that are mostly located in the spleen and bone marrow react directly or indirectly on different pathogen-associated molecular patterns (PAMPs) as well as damage-associated molecular patterns (DAMPs). This leads to an increased cytokine and chemokine production and activation of other immune cells. Furthermore, these stimuli can also induce epigenetic modifications and metabolic adaptations which cause innate inflammatory memory as well as trained myelopoiesis. These stimulated cells in turn have a direct or indirect effect on the development and progression of various CVDs, such as atherosclerosis, myocardial infarction, or aneurysms. Parts of the figure were drawn using pictures from Servier Medical Art. Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License (https://creativecommons.org/licenses/by/3.0/ (accessed on 7 January 2024)).