The macrophage senescence hypothesis: the role of poor heat shock response in pulmonary inflammation and endothelial dysfunction following chronic exposure to air pollution.

Abstract

Cardiovascular diseases (CVD) have been associated with high exposure to fine particulate air pollutants (PM2.5). Alveolar macrophages are the first defense against inhaled particles. As soon as they phagocytize the particles, they reach an inflammatory phenotype, which affects the surrounding cells and associates with CVD. Not coincidentally, CVD are marked by a depleted heat shock response (HSR), defined by a deficit in inducing 70-kDa heat shock protein (HSP70) expression during stressful conditions. HSP70 is a powerful anti-inflammatory chaperone, whose reduced levels trigger a pro-inflammatory milieu, cellular senescence, and a senescence-associated secretory phenotype (SASP). However, whether macrophage senescence is the main mechanism by which PM2.5 propagates low-grade inflammation remains unclear. In this article, we review evidence supporting that chronic exposure to PM2.5 depletes HSR and determines the ability to solve the initial stress. When exposed to PM2.5, macrophages increase the production of reactive oxygen species, which activate nuclear factor-kappa B (NF-κB). NF-κB is naturally a pro-inflammatory factor that drives prostaglandin E2 (PGE2) synthesis and causes fever. PGE2 can be converted into prostaglandin A2, a powerful inducer of HSR. Therefore, when transiently activated, NF-κB can trigger the anti-inflammatory response through negative feedback, by inducing HSP70 expression. However, when chronically activated, NF-κB heads a set of pathways involved in mitochondrial dysfunction, endoplasmic reticulum stress, unfolded protein response, inflammasome activation, and apoptosis. During chronic exposure to PM2.5, cells cannot properly express sirtuin-1 or activate heat shock factor-1 (HSF-1), which delays the resolution phase of inflammation. Since alveolar macrophages are the first immune defense against PM2.5, we suppose that the pollutant impairs HSR and, consequently, induces cellular senescence. Accordingly, senescent macrophages change its secretory phenotype to a more inflammatory one, known as SASP. Finally, macrophages' SASP would propagate the systemic inflammation, leading to endothelial dysfunction and atherosclerosis.