Inclusion bodies enriched for p62 and polyubiquitinated proteins in macrophages protect against atherosclerosis

The release of proinflammatory cytokines, such as IL-1β, by macrophages increases the size and number of atherosclerotic plaques. Macrophages in atherosclerotic plaques have a defect in autophagy, a process that eliminates dysfunctional proteins, and Sergin et al. showed that p62, a chaperone protein involved in autophagy, sequestered polyubiquitinated proteins in cytoplasmic inclusion bodies in macrophages. Macrophages lacking p62 released more IL-1β, and one of the proteins required for the production of IL-1β partially colocalized with these inclusion bodies. In a mouse model of atherosclerosis, p62 deficiency increased macrophage infiltration in atherosclerotic plaques and exacerbated atherosclerosis. Thus, enhancing the function of p62 to promote the sequestration of polyubiquitinated proteins could prevent macrophages from exacerbating atherosclerosis.