INTRODUCTION
Air pollution is a global concern with detrimental effects on health and
a significant socioeconomic burden worldwide. Approximately 4.2 million
people die every year due to exposure to a specific air pollutant,
particulate matter with aerodynamic diameters ≤ 2.5 micrometer
(PM2.5) (1 ). Elevation of PM2.5is a risk factor associated with prevalence of inflammatory diseases
such as asthma (2, 3 ). However, the mechanisms underlying
PM2.5 effects on asthma prevalence are unclear.
Asthma is the most common chronic disease among children, typically
associated with inflammation of the airways and massive structural
changes collectively called airway remodeling (4 ). Despite
various endotypes of asthma, eosinophilic-rich type 2 immunity is a
characteristic feature of the disease in nearly half of the patients.
Type 2-low asthma is associated with neutrophilic inflammation and
refractoriness to corticosteroids (5 ). However, the role of
monocytes in asthma has remained to be fully understood. It has been
previously reported that monocytes accumulate in the airways of children
with fatal asthma attacks (6 ). In addition, our previous studies
showed that circulating monocytes are enriched in adolescents highly
exposed to PM2.5 (7 ). Deep phenotyping of
circulating monocytes in healthy versus asthmatic children exposed to
various levels of PM2.5 may uncover a specific endotype
of the disease.
Monocytes encompass a heterogeneous population that can be divided into
distinct subsets based on expression of immune markers under
inflammatory conditions (8 ). We postulated that immune signatures
reflecting phenotypic and functional changes of circulating monocytes
differ in healthy versus asthmatic children exposed to low versus high
levels of PM2.5. These immune signatures may provide
novel biomarkers to better stratify disease progression and outcomes,
particularly in children. Furthermore, they may enable development of
treatments for patients living in highly polluted areas, which is an
unmet clinical need.
Monocytes undergo innate training, a cellular process by which they are
educated to respond differently to secondary stimulation compared to the
initial encounter (9 ). This process is tightly regulated by
epigenetic reprogramming. Diverse triggers of epigenetic reprogramming
for trained immunity include β-Glucan (10 ), viral infections
(11 ), catecholamines (12 ), and Bacillus Calmette–Guérin
(BCG) vaccine (13 ). It is not known whether particulate
pollutants are able to train innate immune cells to elicit a specific
hyper-inflammatory response that could eventually predispose individuals
to inflammation via epigenetic mechanisms such as histone modifications
(10, 14 ). Acetylation of histone 3 at lysine 27 residue (H3K27ac)
is a canonical epigenetic mark that distinguishes active enhancers from
inactive/poised enhancer elements and contributes to underlying
induction of trained immunity in monocytes (10, 15, 16 ).
In this study, we compared circulating monocytes from healthy versus
asthmatic children exposed to varying levels of ambient
PM2.5 to determine differences in expression of
monocyte-specific markers as detected by mass cytometry time-of-flight
(CyTOF). In addition, we postulated that fine particulate pollutants
provoke trained immunity characterized by elevation of pro-inflammatory
mediators in circulating monocytes after stimulation with house dust
mite serving as an asthma-relevant aeroallergen in vitro . Using
chromatin immunoprecipitation sequencing (ChIP Seq), we further aimed to
understand whether pollutant-induced trained immunity in monocytes is
mediated via regulation of histone modifications, particularly H3K27ac.