Neuroinflammation Induced by Wildfire Smoke Exposure: Unraveling Endothelial Responses and Inflammatory Resolution


Wildfires have become an escalating environmental concern, with the acres burned annually doubling since 1985. The resulting wildfire smoke is a complex mixture of toxic components arising from diverse combustion sources.

This smoke significantly deteriorates air quality across the country, triggering numerous health issues. While the link between wildfire smoke and cardiovascular, pulmonary, ocular, nasal, and neurological outcomes is established, the mechanisms underlying these neurological effects remain enigmatic.

Neuroinflammation and Pollutant Exposure

Emerging research has highlighted a connection between wildfire smoke exposure, neuroinflammation, and pollutants like ozone and diesel emissions. This association becomes more evident when considering acute and subchronic exposures. Neurological consequences of these exposures are hypothesized to stem from pollutants interacting with the lungs, leading to pulmonary proteolysis. Subsequently, fragmented peptides generated from this process may infiltrate the circulation and disrupt the blood-brain barrier (BBB) integrity, triggering neuroinflammatory responses.

Blood-Brain Barrier Phenotypes and Inflammatory Signaling

The BBB is a complex interface comprising endothelial cells and pericytes surrounded by astrocytic end-feet, serving to regulate CNS separation from peripheral circulation. Disturbances in the BBB can lead to neuroinflammation. Recent studies have identified two distinct populations of BBB endothelial cells marked by CD31 expression levels. Notably, a proinflammatory phenotype characterized by reduced relative CD31 is linked to inflammatory responses. In the context of wildfire smoke exposure, these responses manifest as upregulated intercellular adhesion molecule-1 (ICAM-1) and chemokine C–C motif ligand 2 (CCL2), subsequently activating astrocytes and microglia.

Neuroinflammation Resolution Dynamics

Previous research delving into a 20-day exposure to natural wildfire smoke particles showed alterations in neurovascular endothelial cell phenotypes. Specifically, the CD31Hi (anti-inflammatory) cells exhibited reduced levels of CCL2, inducible nitric oxide synthase, and tumor necrosis factor-α (TNFα). In contrast, CD31Med expressing endothelial cells showed increased expression of the same inflammatory proteins, suggesting a transition from induction to resolution of the inflammatory response.

Peripheral Immune Responses and Transmigration Signals

Leukocyte function-associated antigen-1 (LFA-1) and CCL2, expressed by peripheral immune cells, play a crucial role in transmigration across the BBB into the CNS. This interaction is a key mechanism for peripheral immune invasion into the neurological milieu. Furthermore, vascular cell adhesion molecule-1 (VCAM-1) also mediates peripheral immune infiltration. Distinct markers such as Ly6C on neutrophils and microglial precursors, along with activated microglia, further influence this process.

Understanding Neuroinflammation Dynamics

Prior studies have highlighted the intriguing observation that although wildfire smoke exposure primarily induces modest pulmonary inflammation, it leads to significant neuroinflammatory sequelae. These include microglial activation, peripheral immune infiltration, and altered neuroprotective metabolites. To shed light on the timing of resolution of this neuroinflammation, a novel approach involved replicating biomass smoke inhalation exposure in a controlled laboratory setting.

Methodology: Investigating Inflammatory Resolution

Utilizing a serial euthanasia study design, researchers aimed to dissect the temporal dynamics of the inflammatory endothelial response and its resolution. This investigation relied on advanced techniques such as flow cytometry and metabolomics approaches. These methodologies facilitated the precise characterization of endothelial cell phenotypes and the detection of neuroinflammatory markers.


In conclusion, the escalation of acres burned by wildfires has led to a surge in wildfire smoke exposure, impacting air quality nationwide. The resulting neuroinflammation, now linked to neurological outcomes, is a multi-faceted phenomenon intricately intertwined with pulmonary proteolysis, blood-brain barrier disruption, and immune cell transmigration.

By replicating these exposures in a controlled laboratory setting and employing cutting-edge techniques, researchers are unraveling the timeline of inflammatory resolution, contributing to a deeper understanding of the complex interplay between pollutants, the lungs, and the central nervous system. This knowledge is essential for developing strategies to mitigate the neurological consequences of wildfire smoke exposure and to safeguard public health.

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