摘要：Background: Exposure to ambient fine particulate matter (PM2.5) is associated with cardiovascular mortality, but underlying pathophysiologic mechanisms are not fully understood. Hypothalamic inflammation, characterized by the activation of Inhibitor kappaB kinase 2/Nuclear factor kappaB (IKK2/NF - κB) signaling pathway, may play an important role in the pathogenesis of cardiovascular diseases. We recently demonstrated that hypothalamic inflammation is increased in mice exposed to concentrated ambient PM2.5 (CAP). Objectives: In the present study, we used a neuron-specific IKK2 knockout mouse model to examine the role of neural IKK2 expression and hypothalamic inflammation in the pathophysiologic effects of PM2.5. Methods: We assessed inflammatory and vascular responses in Nestin - creIKK2flox/flox (IKK2Neu-KO) and littermate Nestin - creIKK2flox/+ (control) mice after 4 mo of exposure to filtered air (FA) or CAP. Results: CAP exposure was associated with significantly higher tumor necrosis factor-α (TNFα) and interleukin (IL)-6 mRNA in the hypothalamus of control mice, but not IKK2Neu-KO mice. In addition, CAP exposure–induced increases in bronchoalveolar lavage fluid (BALF) leukocytes, pulmonary macrophage infiltration and IL-6 expression, plasma TNFα and IL - 1β levels, adipose macrophage infiltration and IL - 1β expression, and endothelial dysfunction were reduced or absent in IKK2Neu-KO mice compared with controls. Conclusions: Our findings support a role of neural IKK2 in CAP exposure–induced local and systemic pro-inflammatory cytokine expression, pulmonary and adipose inflammation, and endothelial dysfunction, thus providing insight into pathophysiologic mechanisms that may mediate effects of PM2.5 exposure. https://doi.org/10.1289/EHP2311
