The TREM2 Dependent and Independent Effects of Ozone on Immune Cell Trafficking in the Lung-Brain Axis

Abstract

Air pollution remains a major health threat, responsible for 8.1 million deaths globally and ranking as the second leading cause of death in 2021. Ozone (O3), one of the six main pollutants defined by the Clean Air Act of 1970, has been linked to various health issues, including respiratory and cardiovascular diseases, as well as cognitive decline. Because O3 is confined to the respiratory tract after inhalation and unable to reach the brain directly, its toxicity to distant organs is thought to arise from a cascade of byproducts generated in the lungs. This suggests the pulmonary immune response may contribute to O3-induced effects on the central nervous system (CNS), a concept known as the Lung-Brain Axis. O3 reacts in the lungs, producing reactive oxygen species (ROS) that trigger oxidative stress and inflammation. These ROS can spread throughout the body, leading to widespread oxidative stress and damage. The CNS is particularly vulnerable to oxidative stress, which is closely associated with neuroinflammation. Recent studies have highlighted the role of Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) as a key immune signaling hub, particularly in Alzheimer's Disease (AD) due to its implications in AD pathology and neuroinflammation. However, little research has explored TREM2's role in other myeloid cells or its involvement in the Lung-Brain Axis. This study investigates TREM2 and its adapter protein, DAP12, in O3-driven immune cell trafficking across the Lung-Brain Axis. The findings show that O3 exposure alters immune cell dynamics in the lungs and lymph nodes and that Trem2-deficient mice exhibit transcriptional changes in both pulmonary and neuroimmune responses. These results highlight the complex interplay of TREM2-dependent and independent pathways in O3-induced immune responses, shedding light on how peripheral immune activity can influence the neuroimmune environment and linking environmental factors to CNS health and disease.