Concentrated Ambient PM2.5-Induced Inflammation and Endothelial Dysfunction in a Murine Model of Neural IKK2 Deficiency

Abstract

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

Short-term exposure to air pollution (PM2.5) induces hypothalamic inflammation, and long-term leads to leptin resistance and obesity via Tlr4/Ikbke in mice

“…Our results are in accordance with previous studies that showed the pro-inflammatory effect of PM 2.5 in the hypothalamus 16,17,42 . Several elegant studies demonstrated that central IKKβ, which is part of the canonical TLR4 pathway, was likely involved in the inflammatory signals in the hypothalamus of mice exposed to PM 2.5 chronically.…”

“…In another study, 16 weeks of PM 2.5 exposure increased pulmonary, systemic and adipose tissue inflammation as well as induced endothelial dysfunction. The deletion of IKKβ by using nestin cre and IKKβ flox flox mice decreased these inflammatory responses 16,17,42 . So far, these mentioned studies have focused on effects of chronic exposure to PM 2.5 on the peripheral disarrangements.…”

Metabolomics analysis of a mouse model for chronic exposure to ambient PM2.5

“…These clusterings strongly suggest that chronic CAP exposure markedly altered the circulating metabolome. They are consistent with numerous previous studies showing that chronic ambient PM 2.5 exposure correlates with various systemic and/or extra-pulmonary effects (Chen et al, 2017;Chen et al, 2018;Gorr et al, 2014;Hu et al, 2017;Sancini et al, 2014;Zhang et al, 2017). Notably, in spite of those numerous studies investigating the toxicity of chronic ambient PM 2.5 exposure, its biomarker(s) has not yet been established.…”

“…Specifically, C57Bl/6J female mice (3-week-old, 11/group and 22 in total) were purchased from the Animal Center of Fudan University (Shanghai, China) and acclimated in the animal facility for 2 weeks before exposure to FA or CAP. The group size of 11 was determined through the power analysis using the previously published effect of CAP exposure on the circulating IL-6 (Chen et al, 2018). As per the calculation with an online calculator (www.stat.ubc.ca/~rollin/stats/ssize/ n2.html), the statistic power is 0.9.…”

Exposure to PM2.5 during pregnancy or lactation increases methylation while reducing the expression of Pdx1 and NEUROG3 in mouse pancreatic islets

“…has been associated with an increased risk for atherosclerosis, hypertension, cardiovascular diseases, and diabetes [2][3][4].…”