ERK5 Activation in Macrophages Promotes Efferocytosis and Inhibits Atherosclerosis

Abstract

Background Efferocytosis is a process by which dead and dying cells are removed by phagocytic cells. Efferocytosis by macrophages is thought to curb the progression of atherosclerosis, but the mechanistic insight of this process is lacking. Methods and Results When macrophages were fed apoptotic cells or treated with pitavastatin in vitro, efferocytosis-related signaling and phagocytic capacity were upregulated in an ERK5 activity–dependent manner. Macrophages isolated from macrophage-specific ERK5-null mice exhibited reduced efferocytosis and levels of gene and protein expression of efferocytosis-related molecules. When these mice were crossed with low-density lipoprotein receptor−/− mice and fed a high-cholesterol diet, atherosclerotic plaque formation was accelerated, and the plaques had more advanced and vulnerable morphology. Conclusions Our results demonstrate that ERK5, which is robustly activated by statins, is a hub molecule that upregulates macrophage efferocytosis, thereby suppressing atherosclerotic plaque formation. Molecules that upregulate ERK5 and its signaling in macrophages may be good drug targets for suppressing cardiovascular diseases.

Dipeptidyl Peptidase‐4 Inhibitor Anagliptin Prevents Intracranial Aneurysm Growth by Suppressing Macrophage Infiltration and Activation

“…Statins robustly activate ERK5 in endothelial cells, preventing endothelial dysfunction 14. In macrophages, ERK5 activation by statins enhances efferocytosis and plays a key role in atherosclerotic plaque formation in hyperlipidemic mice 15. Our study revealed that, similar to statins, anagliptin activates ERK5 in macrophages and inhibits inflammatory activation of RAW264.7 macrophage‐like cells.…”

“…ERK5 activation plays key roles in the anti‐inflammatory effect of statins in endothelial cells,14 and in macrophages, statins increase ERK5 kinase activity, resulting in increased capacity to phagocytose apoptotic cells and inhibited atherosclerotic plaque formation 15. Notably, anagliptin robustly activated ERK5 in RAW264.7 cells regardless of lipopolysaccharide treatment (Figure 4A).…”

MerTK cleavage limits proresolving mediator biosynthesis and exacerbates tissue inflammation

“…We now add SPM synthesis to MerTK's repertoire of proresolving functions. In this context, understanding the regulation of MerTK is a critical issue, with most studies focusing on its transcriptional induction (e.g., by glucocorticoids, LXR, and ERK5) (46)(47)(48). The discovery of ADAM17-induced MerTK cleavage raised the possibility of a posttranscriptional mechanism (21,22), but in vivo proof was lacking because currently available tools (e.g., ADAM17 inhibitors) are nonspecific.…”

sNASP inhibits TLR signaling to regulate immune response in sepsis

“…Peritoneal macrophages and BMDMs were cultured as previously described (43). The human monocyte THP-1 cell line (ATCC TIB-202, American Type Culture Collection [ATCC]) was cultured in RPMI-1640 medium (ATCC 30-2001, ATCC) supplemented with 2 mM glutamine, 10% FBS, and 1% penicillin and streptomycin.…”