Role of Innate Immune System in Environmental Lung Diseases

Abstract

The lung mucosa functions as a principal barrier between the body and inhaled environmental irritants and pathogens. Precise and targeted surveillance mechanisms are required at this lung-environment interface to maintain homeostasis and preserve gas exchange. This is performed by the innate immune system, a germline-encoded system that regulates initial responses to foreign irritants and pathogens. Environmental pollutants, such as particulate matter (PM), Ozone (O₃), and other products of combustion (NO₂, SO₃, etc.) both stimulate and disrupt the function of the innate immune system of the lung, leading to the potential for pathologic consequences.

Purpose of review:

The purpose of this review is to explore recent discoveries and investigations into the role of the innate immune system in responding to environmental exposures. This focuses on mechanisms by which the normal function of the innate immune system is modified by environmental agents leading to disruptions in respiratory function.

Recent findings:

This is a narrative review of mechanisms of pulmonary innate immunity and the impact of environmental exposures on these responses. Recent findings highlighted in this review are categorized by specific components of innate immunity including epithelial function, macrophages, pattern recognition receptors, and the microbiome. Overall, the review supports broad impacts of environmental exposures to alterations to normal innate immune functions and have important implications for incidence and exacerbations of lung disease.

Summary:

The innate immune system plays a critical role in maintaining pulmonary homeostasis in response to inhaled air pollutants. As many of these agents are unable to be mitigated, understanding their mechanistic impact is critical to develop future interventions to limit their pathologic consequences.

Introduction

As a mucosal surface, the lung is at the interface between the external and internal environments and is continuously exposed to a variety of foreign materials including pathogens, particulates, and toxicants. Addressing these exposures while maintaining homeostasis to preserve principal functions (e.g. gas exchange) requires highly coordinated immune surveillance. This surveillance directs targeted and appropriate responses to foreign materials while limiting excessive inflammation that can lead to tissue damage and disease. This effort largely is the role of the innate immune system. The innate immune system is composed of cellular and humoral components that are responsible for initial responses to inhaled foreign materials [1]. These responses are germline encoded, meaning that they are genetically inherited and do not require prior exposure to initiate responses. Innate immunity includes physical and mechanical barriers, pattern recognition receptors, and cellular/humoral components. Innate immune activation directs targeted inflammatory cascades that initiate inflammation to pathogens while also facilitating resolution to limit lung injury. When functioning appropriately the innate immune system allows the lung to appropriately defend itself while also maintaining homeostasis.

To a large extent, lung disease reflects a failure of normal immune mechanisms that maintain homeostasis. When homeostasis is not maintained, inflammation becomes dysregulated and can persist. This chronic inflammation can then result in ongoing lung damage frequently observed in chronic lung disease. This process has been observed with innate immune system dysregulation. Research continues to demonstrate that dysregulated innate immunity occurs in response to environmental pollutants [2, 3]. This appears to be the result of pollutants coopting normal innate immune signaling pathways. A consequence of innate immunity being germline encoded is that innate immunity has not adapted to evolutionarily novel exposures, such as products of combustion and other industrial materials that have become central parts of modern life. As seen in Figure 1, the consequence of this can be inappropriate or prolonged inflammation that can cause incident respiratory disease or exacerbate established disease. The impacts can be at a cellular level but also in the context of organ function and lung disease (Highlights of important recent papers in Table 1). This is best evidenced by clear associations between ambient air pollution exposures and airway diseases such as asthma [14–18], chronic obstructive pulmonary disease (COPD) [19–23], and cystic fibrosis [24–26]. Much of this epidemiology has focused on exacerbations of these diseases, however there is developing evidence that suggest air pollution may result in incident airway disease (as discussed in an recent American Thoracic Society report [27]). Therefore, understanding the interactions between environmental exposures and the innate immune system is critical to improving the care of these diseases and limiting the severity of their clinical course.

Figure 1.

Air pollution induction of adverse effects on innate immunity. (Created with BioRender.com)

Table 1.

Innate immunity impacts following exposure to air pollutants.

Innate Immunity Component	Environmental Exposure	Finding	Source
Airway Surface Liquid	Diesel Particulate Matter (DPM)	DPM inhibits ASL secretion and increases ASL viscosity. In this study, naringin, a dihydroflavone, attenuated DPM-induced injury, reduced viscosity by decreasing MUC5AC and protein secretion, and positively regulated apical CFTR insertion and activity.	[4]
	Coal Fly Ash (CFA)	In this study, CFA was exposed to pig and human airway explants. They observed increased bacterial survival following CFA exposure through a reduction of antimicrobial peptides in the ASL.	[5]
Epithelium	Ozone (O3)	This study evaluated ozone effects on integrity of the respiratory epithelium. They observed following ozone an increase in epithelial barrier proteins (claudins). This was associated with evidence of reduced resistance in air-liquid interface cultures following in vitro exposure.	[6]
	Diesel Exhaust Particulate (DEP)	Human bronchial epithelial cells and lung fibroblasts were co-cultured and exposed to DEP. Following exposure, there was evidence of transepithelial stress via a redox imbalance on the lung fibroblasts via a non-direct exposure.	[7]
Macrophages	Particulate Matter (PM)	PM exposure to macrophage increased expression of enzymes for xenobiotic metabolism, oxidative stress, cytokine production and release of extracellular vesicles. These macrophage-derived extracellular vesicles increased IL-8 expression when exposed to BES2B cells, suggesting a mechanism for cross-talk.	[8]
	Particulate Matter (PM)	Explored the effects of different macrophage subsets following short term (4 weeks) and chronic (32 weeks) PM2.5 exposures. As opposed to short term exposure, chronic exposure, resulted in replacement of alveolar macrophages with macrophages derived from bone marrow intermediates. This occurred, in part, because the resident alveolar macrophages had heightened apoptosis and diminished replication following exposure.	[9••]
Host Genetic Factors	Traffic-related air pollution	Genetically susceptible middle-aged individuals, lacking GSTT1, may be at a greater risk of allergic sensitization, asthma, and lower lung function follow exposure to traffic-related air pollution.	[10]
Microbiome	Ozone (O3)	Reduced dietary fiber in female mice resulted in augmented responses to ozone. There were notable changes in the 16s RNA sequencing of fecal DNA that also differed by sex, suggesting that alteration of gut bacterial taxa may impact the pulmonary response to ozone exposure	[11]
	Ozone (O3)	Ablation of the gut microbiome resulted in greater airway hyperresponsiveness (AHR) in male mice after O3 exposure. Female mice raised in cages conditioned by adult male mice developed increased AHR. These data suggest sex specific differences in microbiome-related response to O3 exposure.	[12••]
	Particulate Matter (PM)	C57BL/6 mice were exposed to filtered air or concentrated PM for 8h/day, 5 days/week for 3 weeks. Gastrointestinal track microbiota were assessed. Demonstrated that PM altered the microbiota specifically in the beta-diversity from proximal to distal parts of the intestine.	[13]

The purpose of this review is to explore recent developments in our understanding of the role of the innate immune system in environmental lung disease, specifically allergy and asthma. We will focus our review by dissecting the innate immune system into individual components and provide current updates on their relationship to environmental lung disease; specifically, airway epithelium, macrophages, pattern recognition molecules, and the microbiome.

Epithelium/Respiratory Mucosa

The respiratory mucosa is a multi-component defense system, comprised of airway surface liquid and mucus, epithelial cell tight junctions, and immune receptors, which serves as a barrier to environmental pollutants, irritants and pathogens. Loss of epithelial barrier functions or modification of epithelial responses can facilitate penetration of particles or pathogens to the distal airspaces and lead to tissue damage. Disruption of the epithelial barrier has been hypothesized as a mechanism that allows continued exposure to environmental triggers to worsen airway hyper-responsiveness, allergy, and asthma [28]. Environmental pollution exposures have been broadly shown to alter epithelial integrity and function, modify particulate clearance and uptake, activate pro-inflammatory toll-like receptors (TLRs), and increase production of reactive oxygen species [29].

Airway Surface Lining Liquid

The initial impact of an environmental exposures occurs at the airway surface liquid (ASL). The ASL is comprised of peptides, enzymes, and mucins, which collectively have antimicrobial and particle/pathogen clearance functions. In healthy subjects, the ASL traps and facilitates clearance of environmental allergens or irritants. Changes in ASL composition can facilitate inflammation to otherwise benign exposures. The impact of environmental exposures on the ASL has been relatively under-explored but recent data suggests it has important implications for immunity. This can occur through direct effects on ASL components. For example, O₃, reacts with molecular (proteins, antioxidants, hyaluronan polymers) elements in the ASL to alter their functional properties [29–31]. This includes effects such as fragmentation of hyaluronan [32, 33], oxidation of phospholipids [34, 35], and generation of reactive oxygen species [36]. The effects can promote inflammation through engagement of specific pattern recognition receptors [33]. Alternatively, environmental exposures can alter the composition of the ASL. Vargas Buonfiglio et al. demonstrated that coal fly ash particulate matter interacted with antimicrobial proteins and peptides, absorbing them on their surface to facilitate increased pathogen survival in the airspace [5]. Consistent with this, particulate matter exposure reduced expression of two antimicrobial peptides in the ASL, salivary agglutinin [37] and β-defensin [38]. Finally, data suggest that air pollution can alter the secretion of ASL fluid. Shi et al. demonstrated that diesel particles reduced ASL secretion leading to enhanced viscosity [4]. Normally bacteria stimulate ASL secretion, therefore, this could represent a potential link between environmental exposures and acute exacerbations of lung disease such as CF [39]. Furthermore, as chronic lung diseases are known to have alterations in basal ASL composition, it is possible that basal changes in ASL composition in chronic lung diseases could worsen the pulmonary impact of environmental exposures.

Epithelial Integrity

Below the ASL, the airway epithelium forms a barrier between the airspace and the interstitium to segregate the external environment from host tissues. Rather than being a strict barrier, the epithelium directs regulated traffic of electrolytes, peptides and large macromolecules. Some of this occurs via transcellular mechanisms, however the vast majority of this trafficking is paracellular. Paracellular trafficking is regulated by the interaction of barrier proteins within the tight junction. Tight junction integrity is known to be affected by environmental exposure and is an area of active research [40]. Michaudel and colleagues demonstrated that a single in vivo rodent O₃ exposure (1 ppm for 1 hr) resulted in an immediate and rapid disruption of the epithelial barrier, reflected in increased BALF protein [41]. This was followed by a delayed increase in BALF protein associated with trafficking of immune cells into the airspaces. This delayed increase was associated with an increase in the tight junction components E-cadherin, ZO-1, and claudin-4, and this increase was dependent on IL-33/ST2 signaling. Other environmental toxins, including diesel exhaust, have been implicated in altering tight junctions. Smyth et al. recently demonstrated that in vitro exposure of human bronchial epithelial cells to diesel exhaust particle (DEP) resulted in reduced epithelial barrier integrity as measured by a reduction in transepithelial electrical resistance (TEER) and an increase in FITC-Dextran transit [42]. This correlated with a reduction in tricellulin transcription, which is a tight junction protein regulating epithelial integrity. To further confirm the role of tricellulin, siRNA knockdown of tricellulin recapitulated the DEP effect on epithelial permeability. Zinc oxide, a common man-made nanoparticle, has also been shown to increase barrier dysfunction, and reduce the continuity of tight junction proteins like claudin 5 and ZO-1 [43]. The summative effect of these responses limit normal regulation of the trafficking between the external and internal environments and can lead to exacerbated or ineffective responses to injurious agents [40].

Mucociliary clearance

Mucociliary clearance aids in the maintenance of the epithelial barrier. Coordinated ciliary movements results in the movement of environmental pollutants and inhaled particulate material from the deeper areas of the lung to the pharynx for physical clearance [44]. Previous work exploring alterations in mucociliary clearance have largely focused on cigarette smoke, which is well known to affect the structure and function of ciliated epithelium and therefore alter the innate immune response [45]. Recently, there have been focused studies investigating the role of urban air pollution on nasal clearance and airway inflammation and the impairment of nasal clearance among wood industry workers, but impact of environmental exposures on pulmonary mucociliary clearance are an area that requires further investigation [46, 47]. This area of research represents a gap in the current understanding of the impact of environmental lung disease on the innate immune system.

Epithelial Cytokines and Secreted Factors

Though airway epithelial cells are principally studied for their barrier and mucociliary functions, they are also important sources of secreted factors that regulate immune responses. Additionally, environmental exposures can cause inappropriate release of these factors to negatively impact normal immune responses and the maintenance of homeostasis [48]. Cytokine production depends on the type of environmental stimuli, including the dose and the duration of exposure. For example, it is well established that particulate matter (PM) and O₃ exposures cause release of pro-inflammatory mediators such as IL-6 and IL-8 and cyclooxygenase-2 from the airway epithelium. Their release appear to be coordinated through mitogen activated protein kinases (MAPKs) activation of NF-κB [49–52]. However, Tripathi el al. observed that lower doses of PM_2.5 or repeat exposures led to a change in the cytokine profile from IL-6 and TNF to IL-13 and TGFβ1 [53]. In addition to the exposure dose, host genetics may modify cytokine responses. Bowers et al. demonstrated that production of IL-8 was variable in airway epithelial cultures from distinct human donors [54]. Furthermore, this variability associated with the level of ERK1/2 activation but did require p38 activation for robust IL-8 production. Alternatively, interactions with other innate immune cells could impact epithelial cytokine responses to environmental stimuli. Bauer et al. demonstrated that A549 cells co-cultured with alveolar macrophages increased IL-8 production [55]. Defining the interactions between host genetics and cross talk between innate immune cells still requires investigation to establish mechanistic links.

Recent data has suggested that specific airway epithelium-induced cytokines favor T-helper cell type 2 (Th2) responses [56]. This has focused on IL-25, IL-33, and TSLP, otherwise known as alarmins. Alarmins induce airway inflammation, promote eosinophilic infiltration, and increase airway hyperresponsiveness in both human and animal models [57–60]. Potentially linking environmental exposures with allergic airway disease, alarmin production (i.e. IL-33) has been shown to be increased following particulate matter and O₃ exposure [41]. Recent data suggests that humans with mild allergic asthma exposed to allergens demonstrated increased IL-33 and IL-25 in bronchial mucosa, which correlated with their degree of bronchoconstrictor responses [61]. Due to the prevalence of IL-33 within the epithelium and its role as a bridge between innate and adaptive immune responses [62], it has emerged as a potential target for treatment of allergic asthma. De Grove et al. demonstrated that prophylactic neutralization of IL-33 resulted in attenuation of allergic inflammation after house dust mite exposure in mice [63]. Neutralization of IL-33, therefore, may represent a target for future immunotherapies to manage environmental-induced allergic airways disease.

Beyond cytokine production, epithelial cells can also signal via the release of other cellular constituents. Upon stimulation by exogenous factors like environmental toxicants or cytokines, epithelial cells can utilize extracellular vesicles to transfer microRNAs between cells and promote expression of cell surface molecules such as human leukocyte antigens (HLAs) or co-stimulatory molecules required for immune responses [64]. A potential hypothesis of interest is that vesicular miRNA trafficking leads to downstream effects. It has been suggested that early-life O₃ exposure may result in aberrant programming of the innate immune system via alterations in miRNA expression [65]. Airway epithelial cells derived from rhesus macaques with postnatal O₃ exposure resulted in differential expression of potential IL-6-targeting microRNAs miR-149, miR-202, and miR-410 following LPS challenge. Additionally, a recent study demonstrated that IL-13-stimulated airway epithelial cells secrete epithelial vesicles containing miRNAs (miR-92b, miR-210, and miR-34a) that regulate Th2 differentiation and dendritic cell maturation [66]. These same miRNAs were found in the bronchoalveolar lavage fluid of asthmatic children. Greater understanding of the ability of environmental exposures to regulate extracellular vesicle trafficking and their miRNA composition could allow for targeted interventions to impact innate immune cell crosstalk and activation.

Macrophages

Macrophages are critical innate immune cells with important roles in maintaining homeostasis as well as initiating and regulating inflammation [67]. Macrophage functions are impacted by exposure to air pollutants and other environmental exposures, altering normal inflammatory and resolution responses within the lung [9, 67, 68]. Broadly, these effects have been observed with a variety of air pollutants, including particulate matter as well as O₃ [9, 69–71]. The effects include pro-inflammatory cytokine production and reduced phagocytosis and efferocytosis. Studies continue to dissect these functional responses and the impact of environmental exposures to understand how dysregulated functions can affect pulmonary diseases such as asthma and allergy.

Macrophage Origin/Tissue Location

Increasingly, macrophage functions are considered in the context of their origin and tissue location [72, 73]. In the lung, macrophages are present both in the airspace and the interstitium, exhibiting distinct gene expression patterns and cell surface markers based on their location [74–76]. Additionally, there is evidence suggesting that there are distinct macrophage subsets within these compartments. Detailed evaluation of airspace macrophages by single cell RNA sequencing identified unique airspace macrophage subsets that were conserved across individuals and between sexes, including a subset with metal binding gene expression [77]; suggesting a response to environmental pollutants such as particulate matter [78]. The functions of these individual subsets were not clearly defined but support other studies identifying that macrophages from the upper and lower respiratory track had distinct bioenergetics at baseline and in response to phorbol 12-myristate 13-acetate (PMA) or 1,2-naphthoquinone [79]. In the interstitium, as defined by Hume et al detailing stereology of macrophages in lung tissue, distinct macrophages are located along the bronchi (termed peribronchial), in the alveolar interstitium and also around the vasculature [80]. Additionally, macrophages can be derived from circulating intermediates. This has been described as being via CCR2 dependent recruitment of monocytes that then differentiate into macrophages in the lung. It has been described that these monocyte-derived macrophages may arise from monocytes that trafficked to the spleen [81]. It also has been suggested that with chronic exposure to PM_2.5 these monocyte-derived macrophages can replace tissue-resident macrophages and may function to perpetuate chronic inflammation [9]. These efforts, along with others, have begun to untangle the heterogeneity that exists in the lung and define how the diversity of macrophage functions and origin drive responses to environmental pollutants and environmental lung disease [9, 82–85]. However, developing the detailed tools and methods to explore this in vivo and in humans remains a limitation to understanding these links.

Toll-like Receptor Responses

A principal function of macrophages is to elaborate cytokines to target inflammatory responses and direct normal tissue maintenance functions. This occurs through macrophage’s ability to sense alterations in the external environment. A principal pathway regulating this response is signaling via endogenous and exogenous molecular patterns, frequently termed damage associated molecular peptides (DAMPs) and pattern associated molecular peptides (PAMPs), interacting with pattern recognition receptors such as toll-like receptors (TLRs). This diversity of pattern recognition is a key feature of innate immunity. However, it has been well established that environmental exposures can direct activation of TLRs to generate pro-inflammatory cytokine production [86]. This appears to occur through production of endogenous DAMPs such as reactive oxygen species (ROS), and fragmentation of hyaluronan [87]. Additionally, air pollutants can also upregulate TLR expression or activation to heighten the macrophage responses to these PAMPs and DAMPs, a function known as priming. Priming has been observed in several experimental exposure models [88–94] where it requires toll-like receptor 4 (TLR4) signaling [95], but it has not been explored in humans. To address this, our lab obtained alveolar macrophages by bronchoscopy following laboratory exposure to filtered air and O₃ [96]. Following culture, the alveolar macrophages (AM) were stimulated with either PBS, LPS or PMA. Consistent with murine studies demonstrating priming, O₃-exposed AMs exhibited enhanced TNFα gene expression to LPS or PMA [96]. This was associated with an increase in TLR4 and CD14 expression suggesting similar priming mechanisms between mouse and humans. Beyond priming, recent work by Hussain et al. identified an interaction between TLR4 and TLR5 in pulmonary air pollution responses [97]. They observed that TLR5 directly associates with TLR4 and biases TLR4 signaling to the MyD88 pathway. Furthermore, a dominant negative TLR5 polymorphism reduced macrophage inflammatory responses.

Phagocytosis/Efferocytosis

The clearance of debris and pathogens through phagocytosis, as well as clearance of apoptotic cells via efferocytosis, are critical functions that macrophages perform to maintain homeostasis (previously reviewed in [98, 99]). Prior work supports that macrophage phagocytosis is altered by exposure to pollutants. This includes studies with murine and human exposures to O₃ [100], PM [101], and engineered nanomaterials [102]. Beyond clearance of bacteria and/or debris, macrophages are critical to the clearance of immune cells, particularly those that are apoptotic, through a process termed efferocytosis [103]. Efferocytosis is critical to resolution of inflammation and also the maintenance of homeostasis. Recent data suggests that macrophage efferocytosis is dysregulated in chronic lung diseases such as asthma [104]. Additionally, it is becoming clear that environmental exposures can reduce efferocytosis [94]. A recent study by Hodge et. al. developed a protocol to assess alveolar macrophage efferocytosis in vivo and noted decreased macrophage efferocytosis following exposure to O₃ when compared to filtered air [105]. This may have important implications for understanding mechanisms of inflammation resolution with environmental exposures as efferocytosis is known to induce production of specialized pro-resolving mediators [103]. Though the data supports that environmental exposures impact phagocytosis and efferocytosis the specific mechanisms activated or inhibited remain largely understudied.

Environment and Microbiome Interactions Impacting Innate Immunity

Beyond the cellular components of innate immunity, it has become clear that the composition of local microbial components, or the microbiome, are critical to maintaining homeostasis and can modify innate immune responses. Previous studies have suggested that composition of the microbiome can shape immune responses and modulate Th2 responses [106]. Additionally, a recent study suggests that the airway microbiome composition can be influenced by environmental conditions [107]. Human studies have suggested that childhood microbial exposure decreases asthma susceptibility [108]. Additionally, antibiotic extermination of microbiome or dietary modulation results in increased severity of allergic asthma in animal models [109–111]. Individuals with exacerbation of obstructive lung diseases including asthma have been shown to segregate into distinct clusters based on their microbiomic profile, which correlates with eosinophilic inflammation and likelihood of response to Th2-targeted monoclonal antibody therapies [112]. Specific taxa analyses suggest an enrichment of Haemophilus, Fusobacterium, Neisseria, Porphyromonas, and Sphingomonodaceae among patients with allergic asthma. The presence of bacterial subtypes may reflect steroid responsiveness among patients with Th2 inflammation and asthma [113]. The pulmonary microbiome may also affect innate and adaptive immunity in mice. IL-1α, a key cytokine in pulmonary innate immunity, was demonstrated to be negatively affected by decreased pulmonary microbiome diversity in mice [114]. Other recent studies, including Cho et al, have demonstrated evidence of increased airway hyperresponsiveness (AHR) after alteration of pulmonary microbiome. Following antibiotic-driven microbiome depletion, mice demonstrated attenuation of O₃-induced AHR, decreased epithelial permeability, and decreased BAL neutrophil count [12]. Further work by this group suggested that these effects exhibit sex-dependence [11], raising the question if microbiome effects and efforts to modulate the microbiome might need to consider sex as a response variable. Despite evidence suggesting a role for the microbiome, clinical studies assessing the utility of antimicrobial therapy have not correlated microbiome modification with improvement in asthma symptoms or frequency of exacerbation. For example, the AMAZES trial suggested improvement in asthma exacerbations after treatment with macrolide therapy. However, this improvement was not associated with changes in sputum microbiome content [115]. Consistent with this observation, other studies have demonstrated improvement in symptoms that are independent of changes in sputum microbiome composition [116]. Therefore, the therapeutic efficacy of altering the microbiome in allergic asthma outcomes remains under investigation.

Host and Genetic Factors that Impact Innate Immune Responses

As innate immune responses are germline encoded this suggests that an individual’s genetics can modify potential responses to the environment, termed gene by environment interactions. Recent studies continue to observe these factors that support variability in individual responses to environmental exposures. In addition to genetics, it has become increasingly apparent that host factors including age and sex impact exposure responses [70, 84, 117]. To understand sex-specific effects, our lab acutely exposed male and female mice to filtered air and O₃ for 3 hours. In this study, we observed that male mice developed increased airway hyperresponsiveness (AHR) to methacholine challenge [84]. This observation was consistent with research by another group [12, 118], but not observed in studies by another group where females exhibited enhanced AHR and this was dependent on 17β-estradiol [119, 120]. This could be a result of different timing in the estrous cycle of exposure and phenotyping. As opposed to data support male-predominant AHR responses, female mice exhibit greater airspace inflammation. This was consistent with several studies demonstrating increased inflammation and cytokine mRNA in O₃-exposed female mice, in a mechanism dependent on microRNAs [119–122]. Similar findings have been observed in other air pollutant exposure studies in mice, though at present there is a paucity of data about sex-dependent effects on human exposure studies. To address this, Rebuli et al. exposed 39 healthy adults to woodsmoke particles followed by exposure to live attenuated influenza virus. They observed that the inflammatory responses to these exposures depended on the sex [123]. This highlights that sex needs to be considered a biologic variable in assessing exposure responses and the impact on innate immunity.

Recent developments suggest that beyond gene variants that DNA modifications can also drive individual variability. DNA methylation and histone modifications that influence downstream gene expression can be altered by prior exposures and stressors, including air pollution [124, 125]. A recent study by McCullough et al. characterized basal chromatin modification variability in both non-exposed and O₃ exposed cells. The distinct modifications in both the basal and exposed cells correlated with O₃-induced inflammatory and stress markers; thus, demonstrating individual variability in gene induction following exposure [124]. An additional study also looked at the impact of prenatal exposure to O₃ and NO₂ air pollution. This study defined methylation changes in the cord blood and placenta. While some of the DNA methylation were sex-specific, the genes that were largely affected included those involved in immune and inflammation processes as well as metabolism [125]. This suggests that these epigenetic modifications can define innate immune responses and represent an important consideration to development of environmental lung disease.

Conclusion

Research continues to link the importance of environmental exposures to altered innate immunity and how this can worsen the severity of lung disease. Given the complexity of these responses, efforts need to consider individual components in detail and then scale these into more complex models to define their impacts. Regardless of the complexity, defining mechanisms and associations between innate immune signaling and environmental lung disease offers an incredible opportunity to target these pathways and improve public health.