HMGB1: Comparison in Asthma and in COPD

HMGB1: Comparison in Asthma and in COPD: History

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Subjects: Immunology

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The airway epithelium, through pattern recognition receptors expressed transmembrane or intracellularly, acts as a first line of defense for the lungs against many environmental triggers. It is involved in the release of alarmin cytokines, which are important mediators of inflammation, with receptors widely expressed in structural cells as well as innate and adaptive immune cells. Knowledge of the role of epithelial cells in orchestrating the immune response and mediating the clearance of invading pathogens and dead/damaged cells to facilitate resolution of inflammation is necessary to understand how, in many chronic lung diseases, there is a persistent inflammatory response that becomes the basis of underlying pathogenesis, in particular thymic stromal lymphopoietin (TSLP) and high mobility group box 1 (HMGB1), as key mediators in driving the inflammation of chronic lung diseases, such as asthma and chronic obstructive pulmonary disease (COPD), evaluating the similarities and differences.

TSLP
HMGB1
COPD

1. Introduction

The airway epithelium, the first line of defense against environmental triggers, such as allergens, viruses, pollutants, and microbes, is assuming an increasingly interesting role both regarding knowledge of pathogenesis and the current and possible therapeutic strategies of chronic inflammatory lung diseases. Airway epithelial cells express pattern recognition receptors (PRRs), transmembrane or intracellularly, that are able to recognize highly conserved microbial motifs called pathogen-associated molecular patterns (PAMPs) and host-derived molecular damage-associated molecular patterns (DAMPs) [1,2,3]. PRRs play a key role in recognizing invading threats and in initiating host defense through the rapid production of alarmin cytokines [4,5]. DAMPs released from infected or damaged cells bind to specific DAMP receptors (DAMPRs) that are able to stimulate cell differentiation, cell death, or the secretion of inflammatory or anti-inflammatory cytokines.

In reality, the pulmonary epithelium is complex both functionally and structurally, and is a tightly regulated system. In particular, the various tracts of the respiratory airways are made up of diverse cell types, characterized by an organized network of cell–cell interactions and regulatory mechanisms which are fundamental for maintaining tissue homeostasis and responding effectively to damage [6,7]. Proximal airways consist of specialized epithelial cell populations ranging from simple ciliated cuboidal cells to pseudostratified ciliated, columnar cells, while the distal alveolar region consists of alveolar epithelial cells (AECs) [5]. AECs can be further classified into type I or type II pneumocytes, which are different from a phenotypic and functional point of view. In particular, type I pneumocytes (AECI), which make up about 90–95% of the alveolar surface, play a key role in gas exchange, while type II pneumocytes (AECII) are specialized in the production and secretion of pulmonary surfactants, which are fundamental in preventing alveolar collapse [7,8]. In the lung, epithelial cells localized at the interface between the internal and external environments, carrying out a key role in maintaining tissue integrity such as mucociliary clearance, tight junctions, epithelial adherence, and secretion of antibacterial, antimicrobial, and antiprotease molecules [9,10,11,12,13,14], are exposed to many exogenous stressors, for instance bacterial and viral insult, cigarette smoke, asbestos, and airborne pollutants [15], and many endogenous signals such as oxidative stress [16].

Epithelial cells are essential to regulate immune response and facilitate the resolution of inflammation, restoring tissue homeostasis in response to injury [17], albeit in many chronic lung diseases persistent inflammation, pathological repair mechanisms, and functional tissue architecture destruction may arise [18], where injury to epithelial cells underlies the pathogenesis of many chronic pulmonary diseases [19].

Chronic airway diseases, for instance asthma and chronic obstructive pulmonary disease (COPD), are characterized by various inflammatory phenotypes and an underlying abnormal immune response. These two inflammatory respiratory diseases have similar symptoms, such as dyspnea, cough, and sputum, but differ in pathogenesis, age of onset (young age for asthma, old age for COPD), disease progression, prognosis, and therapeutic strategies. In asthma, the main cells involved are CD4, T-lymphocytes, eosinophils, and mast cells; in COPD, the main cells involved are CD8, T-lymphocytes, and macrophages. In severe cases of both chronic respiratory diseases, there may be an infiltration of neutrophils in the airway walls. The thickening of smooth muscles is typical in large airways in severe asthma and in small airways in COPD. In COPD, there are typical structural alterations, such as epithelial changes, caused by cell metaplasia, mucous membrane changes, and fibrosis of airway walls. Moreover, another feature typical of COPD but not of asthma is the destruction and fibrosis of the alveolar wall [20].

Allergens and pathogens, as well as smoking and further pollutants, act on the lung inducing injury and airway inflammation in a context of genetic predisposition and altered immunity, leading to fixed airflow obstruction and subsequent characteristic symptoms of COPD [19,21]. In COPD, which has a high prevalence and incidence of morbidity and mortality worldwide, a major characteristic of the disease is airway inflammation and this is involved in both progression and pathogenesis, although anti-inflammatory treatment may not be a first-line therapy. In COPD, inflammation can be seen in both the small and large airways and can persist after smoking cessation, probably due to the presence of modified immunity and alterations in the airway microenvironment [20,22].

In the most common phenotypes of COPD, both innate and adaptive immunity are involved, with neutrophilic inflammation. Cigarette smoke exposure, along with other pollutants and allergens, cause airway damage with a consequent release of pro-inflammatory mediators and DAMPs, such as interleukin (IL)-33, thymic stromal lymphopoietin (TSLP), and high mobility group box 1 (HMGB1) [19]. DAMPs, members of the alarmins, which are warning signals released from damaged cells, alert the immune system by activating inflammasomes through interaction with PRRs localized on the plasma membrane, inside endosomes after endocytosis, in the cytosol receptor for advanced glycation end products (RAGE), on retinoic acid-inducible gene 1(RIG-I)-like receptors and nucleotide-binding oligomerization domain 1 (NOD1)-like receptors, and absent in melanoma 2 (AIM2)-like receptors [19].

IL-33 receptor ST2 distribution is modified after exposure to cigarette smoke: it is downregulated in innate lymphoid type-2 cells (ILC2) and upregulated by macrophages that leads to triggering of an IL-33-dependent exaggerated pro-inflammatory cascade [5]. Airway injury alters the barrier function, predisposing the airway to bacterial dysbiosis and infection, which, along with pollutants, induce the switch of ILC2 cells to ILC1 cells, intensifying type-1 inflammation [6,7,19]. While epithelial cells are implicated in inflammatory mediator release, such as tumor necrosis factor (TNF), IL-1β, IL-6, and IL-8, macrophages are involved in releasing pro-inflammatory cytokines and activating the NLRP3 inflammasome with caspase-1-dependent release of IL-1α, IL-1β, IL-33, and IL-18 [23].

Although in COPD the neutrophil phenotype is the most frequent finding, 10–40% of patients with COPD report elevated eosinophilic inflammation in the sputum and/or blood, whose etiology is currently unknown. This eosinophilic inflammation, as in asthma, is related to the risk of severe exacerbations and increased T2-transcriptome signatures.

Similar to neutrophil-associated COPD, eosinophilic COPD includes activation of both innate and adaptive immunity [24,25]. As in asthma, allergies promote Th2 cells that produce IL-4, IL-5, and IL-13. However, eosinophilic inflammation may also be activated by ILC2 cells producing IL-5 and IL-13 in response to PGD2 and the epithelial-derived alarmins IL-33, IL-25, and TSLP released after epithelial injury caused by microbes and pollutants. A further role may be mediated by macrophage-derived IL-33, released after inflammasome activation [24].

Therefore, an important aspect to highlight is that airway inflammation plays a key function in asthma and COPD development, but it is also important to consider that while in COPD there is increased lung inflammation that causes severe damage to the lung parenchyma, in asthma we see local chronic airway inflammation that causes airway remodeling and hyper-responsiveness. In both pathologies, there is the involvement of the adaptive and innate immune system [26]. Injured or dying cells release DAMPs which can warn the immune system through interacting PRRs. DAMPs may be categorized according to their origin. In particular, DAMPs comprise many nuclear proteins, for instance IL-1a, IL-33, and HMGB1, cellular organelles, for example, histones and mitochondria and other cellular components, for instance uric acid, adenosine triphosphate (ATP), heme, HSPs, defensins, haptoglobin, EDN, LL-37, galectin-3 (Gal-3), S100 proteins, hyaluronan, and heparan sulfate [27]. Elevated levels of many DAMPs, including HMGB1, were reported in induced serum and sputum of patients with asthma and COPD in many studies [5,6,19,27,28].

2. HMGB1: Comparison in Asthma and in COPD

HMGB1, the most frequently expressed of the entire HMG family proteins, is a proinflammatory mediator that belongs to the alarmin family, playing a significant role in various acute and chronic immune disorders as a signal of tissue injury and a mediator of inflammation, whose levels are increased in many inflammatory conditions, such as sepsis, cystic fibrosis, and rheumatoid arthritis [29,30]. In particular, HMGB, a non-histone and ubiquitous chromosomal protein found enriched in active chromatin forming part of the high mobility group family of proteins, is encoded by the HMGB1 gene (13q12) in humans and has precise motifs which are DNA-binding domains. In particular, there are four categories of HMGBs (HMGB1-4) [31,32,33].

Many studies have reported an active extracellular release of HMGB1 from cells of the immune system or passively released from injured cells [21,22]. Moreover, studies have described the important role of HMGB1 in regulating several receptors that, through interaction with RAGE and Toll-like receptors (TLRs), are implicated in phosphorylation and in the synthesis of glycation end products. TLRs induce a growth of some cytokines, such as IL-4, IL-6, and TNF-alpha, typical of the innate inflammatory response. Therefore, increased levels of HMGB1 have been associated with several inflammatory diseases [19,28]. Watanabe et al. first tested the HMGB1 level and levels of the endogenous secretory RAGE (esRAGE) in the sputum of 44 asthmatic patients (previous to asthma treatment) and 15 controls, highlighting that sputum levels were notably increased in patients with asthma compared to controls, with a positive correlation between HMGB-1 level and disease severity, while for esRAGE there was no significant difference between mild persistent and severe asthmatic patients [34]. Ferhani et al. described levels of HMGB1 in the fluid from bronchoalveolar lavage (BAL) as also being high in patients with COPD [35]. Straub et al. showed that HMGB1 inhibitors undergo a significant reduction in the ovalbumin-induced rise in response to methacholine in a mouse asthmatic model sensitized and challenged with ovalbumin [36]. Hou C. et al. reported that plasma and sputum concentrations of HMGB1 in patients with asthma and COPD were significantly more elevated than concentrations in control subjects and were significantly negatively correlated with forced expiratory volume in 1 s (FEV1), FEV1 (% predicted). Levels of HMGB1 in the induced sputum of patients with COPD were significantly higher than those of patients with asthma and healthy controls not reporting significant differences in HMGB1 levels between patients with eosinophilic and non-eosinophilic asthma [37]. This latter aspect can be explained by the different sources of HMGB1, such as macrophages, eosinophils, and neutrophils. HMGB1 levels in patients with asthma and COPD reported a positive correlation with neutrophil counts and percentage of neutrophils [38,39]. Hou C. et al. reported also that HMGB1 in induced sputum correlated positively with the percentage of neutrophils and neutrophil count: this is backed up by the finding that neutrophils contribute to higher levels of HMGB1 and that purified HMGB1 may stimulate the dose-dependent chemotaxis of neutrophils [37]. In the literature, it has also been reported that higher numbers of alveolar macrophages can augment levels of HMGB1 in BAL fluid (BALF) from smokers with COPD, and these data are in accordance with Hou C. et al., who reported that macrophage numbers correlated positively with levels of HMGB1 in the sputum of patients with COPD [39,40]. Ferhani et al. also described bronchial epithelial cells as being a potential source of HMGB1 in the airways of patients with COPD, which is in agreement with other studies that reported that hydrogen peroxide may trigger the expression and release of HMGB1 from bronchial epithelial cells in vitro [35,41,42]. Liang et al., having isolated normal human bronchial epithelial cells from the human lung tissue of four patients undergoing lobectomy, highlighted that HMGB1 induces an augmented expression and secretion of TNF-a, TSLP, MMP-9, and VEGF and stimulates activities of the p38 MAPK and ERK1/2 pathways in bronchial epithelial cells by an enhancement of TNF-a, VEGF, MMP-9, and TSLP levels [43]. Cuppari et al. conducted a study on 50 children-adolescents affected by severe, moderate, and mild asthma and 44 healthy controls, reporting a significant increase of sputum HMGB1 levels in patients with asthma compared to healthy controls. Moreover, patients with severe asthma showed higher levels of sputum HMGB1 than patients with mild and moderate asthma. Furthermore, the authors highlighted a positive correlation between total serum IgE levels in the asthmatic group and sputum HMGB1 values in asthmatic children, while reporting an inverse correlation between levels of sputum HMGB1 and indices of lung function [29]. Ojo et al., in 2015, for the first time reported the role of HMGB1 in promoting bronchial epithelial cell wound repair, a process mediated by the production of integrins and ECM proteins [44]. Shang et al. first reported increased levels of plasmatic HMGB1 in patients with COPD compared to healthy subjects [45]. This result was confirmed by other studies such as Ferhani et al. who evaluated HMGB1 as an inflammation marker and analyzed the BAL of 20 never-smoker patients, 20 smokers, and 30 smokers with COPD. Bronchial biopsy and lung tissue sections were used to assess the immunolocalization of HMGB1 and RAGE. The authors observed that BAL levels of HMGB1 were similar in non-smoker healthy patients and in smokers without COPD but there were increased levels in smokers with COPD. A positive correlation between BAL levels of HMGB1 and TNF-RII and IL-1b, and a negative correlation with IL-1RA with no correlation with TNF-α was also reported. High concentrations of HMGB1-positive cells were seen in the bronchial mucosa of smokers with COPD more frequently than in healthy smokers. Lastly, the authors reported an overexpression of RAGE in the smooth muscle and airway epithelium of patients with COPD and that it colocalized with HMGB1 [35]. Pouwels et al. studied HMGB1 levels in the serum of 40 patients with COPD during both an exacerbation and stable phase. An equivalent study was conducted on the inducted sputum of 35 patients reporting no significative differences in levels of sputum, but with increased serum levels of HMGB1 during COPD exacerbations. A gender difference was, moreover, highlighted; in particular, there were high HMGB1 serum levels in women during the acute phase [46]. Cheng et al. reported upregulated TLR4 expression in the lung tissues of mice exposed to cigarette smoke and upregulated HMGB1 levels in lung tissues and airways due to extracellular translocation from the cytoplasm. However, inhibition of HMGB1 expression was related to reduced airway inflammation in mice. Exogenous HMGB1 was related to an increased proinflammatory cytokine production in wild-type mice, but it did not affect proinflammatory cytokine production in TLR4-KO mice [47].

This entry is adapted from the peer-reviewed paper 10.3390/biomedicines11020437

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