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

DiscussionWhen 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 feedba ck, 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.
Source: Inflammation Research - Category: Research Source Type: research