Inflammatory cross-talk between heat events and air pollution

West Virginia University, Morgantown WV

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Abstract

Abstract Air pollution is intricately related to climate change and is among the main drivers of its adverse health outcomes. Epidemiological evidence points towards a link between air pollution and extreme heat events (another main driver of climate-related adverse health outcomes). However, a mechanistic understanding of how these processes may interact at the cellular and organ level is still rudimentary. Addressing climate change-related adverse health outcomes will need a focus on both reduction in global warming and understanding the cellular mechanisms governing the susceptibility. With the proposed studies, we aim to fill in a three-fold knowledge gap: 1) elaborate if air pollution can predispose to a greater inflammatory outcome from extreme heat events, 2) define if heat events make individuals susceptible to adverse outcomes from air pollution exposure, and 3) describe a novel unifying mechanism that governs these processes in the lungs. Based on our preliminary observations, we propose to study nucleotide-binding oligomerization domain, leucine rich repeat containing X1 (NLRX1) as the master regulator for air pollution and heat stress-induced cellular signaling. NLRX1 is mitochondria localized pattern recognition receptor that is a negative regulator of nuclear factor-κB (NF-κB) signaling. Our preliminary data indicate a diminished ability of Nlrx1-/- mice to mount an effective HSP mRNA expression and points towards a role of NLRX1 in mounting an effective adaptive response to environmental stress. The overarching goal of this proposal is to understand the interactive outcomes of heat events and air pollution. The specific hypothesis is that air pollution and extreme heat events induced inflammatory cross-talk is mediated by NLRX1-HSP pathway interactions. To test this hypothesis and leverage our established mixed ultrafine carbon black (CB) and ozone (O3) inhalation co-exposure model, we propose two specific aims: Specific Aim 1: Elaborate the ability of ultrafine CB+O3 inhalation co-exposure to predispose for greater inflammatory outcomes from subsequent heat stress events, Specific Aim 2: Elucidate the ability of heat stress events to predispose for adverse inflammatory outcomes from subsequent ultrafine CB+O3 inhalation co-exposure. Overall, these novel studies will clarify the cross-talk between heat events and posit NLRX1 as a central hub for regulating cellular stress pathways induced after multiple climate change-related exposures (heat stress, ultrafine particles, and O3).