Targeting Macrophage Phenotype for Treating Heart Failure: A New Approach

Abstract

Heart failure (HF) is a disease with high morbidity and mortality rates worldwide and significantly affects human health. Currently, the treatment options for HF are limited, and there is an urgent need to discover new therapeutic targets and strategies. Macrophages are innate immune cells involved in the development of HF. They play a crucial role in maintaining cardiac homeostasis and regulating cardiac stress. Recently, macrophages have received increasing attention as potential targets for treating HF. With the improvement of technological means, the study of macrophages in HF has made great progress. This article discusses the biological functions of macrophage phagocytosis, immune response, and tissue repair. The polarization, pyroptosis, autophagy, and apoptosis are of macrophages, deeply involved in the pathogenesis of HF. Modulation of the phenotypic changes of macrophages can improve immune-inflammation, myocardial fibrosis, energy metabolism, apoptosis, and angiogenesis in HF.

Keywords: apoptosis; autophagy; heart failure; macrophage; polarization; pyroptosis.

Graphical abstract

Figure 1

Macrophage polarization. Macrophages can be categorized into M1 and M2 types. M1 macrophages can be induced by LPS, IFN-γ and TNF-α. They produce IL-1β, IL-6, IL-12, IL-23 and iNOS and promote Th1 type immune response. M2 polarization has four subtypes—M2a, M2b, M2c, and M2d—defined by their inducing molecules and environmental responses. These subtypes play roles in tissue repair, immune regulation, angiogenesis, and tumor cell proliferation.

Figure 2

Macrophage pyroptosis. The process of macrophage pyroptosis primarily depends on inflammasomes and is triggered by different caspases. This leads to the polymerization and shearing of different members of the Gasdermin family, such as GSDMD. The released N-terminal domain of GSDMD binds to membrane lipids to form cell membrane holes, alters the osmotic pressure, and leads to cell swelling until the cell membrane ruptures.

Figure 3

Macrophage autophagy. Macrophages sensing autophagy-inducing signals form intracellular spherical double-membrane autophagosomes, which fuse with lysosomes to form monolipid membrane-coated autolysosomes. Then, misfolded proteins or damaged organelles are degraded by lysosomal hydrolysis enzymes.

Figure 4

Macrophage apoptosis. Stimuli, such as LPS, activate iNOS in macrophages, reducing cell volume, and inducing nuclear sequestration, and chromatin condensation along the nuclear membrane. Then, the nucleus collapses to produce small cell debris or apoptotic bodies.