Unexpected Role of Nonimmune Cells: Amateur Phagocytes.

Effective and efficient efferocytosis of dead cells and associated cellular debris are critical to tissue homeostasis and healing of injured tissues. This important task was previously thought to be restricted to professional phagocytes (PPs). However, accumulating evidence has revealed another type of phagocyte, the amateur phagocyte (AP), which can also participate in efferocytosis. APs are non-myeloid progenitor/nonimmune cells that include differentiated cells (e.g., epithelial cells, fibroblasts, and endothelial cells [ECs]) and stem cells (e.g., neuronal progenitor cells and mesenchymal cells) and can be found throughout the human body. Studies have shown that APs have two prominent roles: identifying and removing dead cells presumably before PPs reach the site of injury and assisting PPs in the removal of cell corpses and the resolution of inflamed tissue. With respect to the engulfment and degradation of dead cells, APs are slower and less efficient than PPs. However, APs are fundamental to preventing the spread of inflammation over a large area. In this review, we present the diversity and characteristics of healthy and non-neoplastic APs in mammals. We also propose a hypothetical mechanism of the efferocytosis of immunoglobulin G (IgG)-opsonized myelin debris by ECs (APs). Furthermore, the ingestion and clearance of dead cells can induce proinflammatory or anti-inflammatory cytokine production, endothelial activation, and cellular fate transition, which contribute to the progression of disease. An understanding of the role of APs is necessary to develop effective intervention strategies, including potential molecular targets for clinical diagnosis and drug development, for inflammation-related diseases.

Downregulation of G3BP2 reduces atherosclerotic lesions in ApoE-/- mice.

BACKGROUND AND AIMS: Atherosclerosis is mainly caused by stress in arterial microenvironments, which results in the formation of stress granules as a consequence of the stress response. As the core protein of stress granules, GTPase-activating protein (SH3 domain)-binding protein 2 (G3BP2) is known to play pivotal roles in tumour initiation, viral infection and Alzheimer's disease, but the role of G3BP2 in atherosclerosis development is poorly understood. Previous studies have shown that vaccination with epitopes from self-antigens could reduce atherosclerotic lesions. Here, we investigated the effect of immunizing ApoE-/- mice with G3BP2 peptides, and whether this immunization exerted an anti-atherogenic effect. METHODS AND RESULTS: In our study, ApoE-/- mice were fed a high-fat diet for 12 weeks from 8 to 20 weeks of age. Then, using a repetitive multiple site strategy, the mice were immunized with a Keyhole limpet haemocyanin (KLH) conjugated G3BP2 peptide for 2 weeks from weeks 16 to 18. High levels of G3BP2 antibodies were detectable before sacrifice. Histological analyses showed that the number of atherosclerotic lesions in ApoE-/- mice was significantly reduced following G3BP2 immunotherapy. The levels of pro-inflammatory cytokines and macrophages were also greatly decreased, while the collagen content of the plaques showed significant increase. Furthermore, knocking down G3BP2 in ApoE-/- mice reduced the number of lesions compared to ApoE-/- mice fed a high-fat diet for eight weeks. In vitro studies demonstrated that G3BP2 regulated ox-LDL-induced inflammation in HUVECs via controlling the localization of IκBα. CONCLUSIONS: Immunization with the G3BP2 peptide antigen or knocking down of G3BP2 significantly decreased early atherosclerotic plaques in the ApoE-/- mouse model of atherosclerosis. G3BP2 is a promising potential target for atherosclerosis therapy.