Abstract—
Lung epithelium is constantly exposed to the environment and is critically important for the orchestration of initial responses to infectious organisms, toxins, and allergic stimuli, and maintenance of normal gaseous exchange and pulmonary function. The integrity of lung epithelium, fluid balance, and transport of molecules is dictated by the tight junctions (TJs). The TJs are formed between adjacent cells. We have focused on the topic of the TJ structure and function in lung epithelial cells. This review includes a summary of the last twenty years of literature reports published on the disrupted TJs and epithelial barrier in various lung conditions and expression and regulation of specific TJ proteins against pathogenic stimuli. We discuss the molecular signaling and crosstalk among signaling pathways that control the TJ structure and function. The Toll-like receptor-4 (TLR4) recognizes the pathogen- and damage-associated molecular patterns released during lung injury and inflammation and coordinates cellular responses. The molecular aspects of TLR4 signaling in the context of TJs or the epithelial barrier are not fully known. We describe the current knowledge and possible networking of the TLR4-signaling with cellular and molecular mechanisms of TJs, lung epithelial barrier function, and resistance to treatment strategies.
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INTRODUCTION
Maintenance of cellular and tissue architecture and function is critical for the normal physiology of body organs and specifically the mucosal gastrointestinal and pulmonary systems, which are constantly exposed to foreign particles, pathogens, toxicants, and environmental stimuli. While recognition and elimination of harmful stimuli are coordinated by nonspecific mechanisms elicited by anatomic structures, such as cilia, immune and non-immune endothelial and epithelial cells can respond in a unique manner against pathologic ligand or stimuli. For simplicity, we have focused on addressing the epithelial layer integrity and function in normal and injured lung during infections and inflammatory conditions. In the respiratory system, the bronchi and bronchioles are mainly equipped with ciliary epithelial cells, mucus-secreting goblet cells, and Clara cells. The alveolar region consists of highly specialized type I and type II epithelial cells. The epithelial cells are connected via tight junction (TJ) proteins on their apical surface at the air–liquid interface. Here we describe the epithelial integrity and coordination of lung function in the context of molecular interplay under normal and injury conditions.
AIRWAY AND ALVEOLAR EPITHELIUM
The human airways can be divided into conducting and respiratory airways. The airway epithelium is pseudostratified in the large airways, becoming columnar and cuboidal in the small airways. The major cells in conducting airways are ciliated, pre-ciliated, basal, goblet, secreted, and indeterminate undifferentiated types. These epithelial cell populations vary at different levels of airways; the numbers of secretory cells increase as the conducting airways start to branch from large to small airways [1]. The alveolar sacs are at the extreme end of respiratory airways. The alveolar epithelium is mainly composed of type I and type II epithelial cells. The type I alveolar epithelial cells are more flattened cells, cover 93% of the alveolar surface, and provide a large surface for gaseous exchange [2]. The type II epithelial cells are specialized cuboidal cells that synthesize surfactant, which is packaged into lamellar body structures and secreted in the alveoli as tubular myelin. The surfactant is a mixture of proteins and lipids and plays an important role in lung function and host defense against invading pathogens and noxious stimulants. The type II epithelial cells serve as progenitor cells for both type I and type II alveolar epithelial cells [2]. An article published by Crystal et al. provides a comprehensive review of airway epithelial cells, stem/progenitor cells, and interaction among cell types [3].
The formation of adhesive contacts between cells is essential for the function of many tissues. This is particularly true for epithelial cells in the lung, which adhere tightly to one another to form an epithelial sheet. This epithelial lining acts as a barrier between airways or alveolar sacs and the underlying interstitial and endothelial layers. The junctional complexes between the neighboring epithelial cells consist of TJs just underneath the apical surface and adherens junctions (AJs) below TJs, at the basolateral sides of the cells [4].
The TJs form the functional and structural boundary that separates apical and basolateral compartments [5], and facilitate intercellular adhesion just underneath the apical surface; control the passage of ions, water, and other molecules; and help maintain the cell polarity [6]. The TJs of the pulmonary epithelium provide the structural basis for the air-blood carrier that prevents invasion of inhaled pathogens and prevents non-selective leakage of fluid into the air spaces [7]. Various studies have revealed the architecture of TJs, which consist of transmembrane and peripheral membrane proteins (Table 1). Transmembrane TJ proteins on airway epithelial cells consist of three main families of proteins: the tight junction associated Marvel proteins (TAMPs), which share myelin and lymphocyte protein (MAL) and related proteins for vesicle trafficking and membrane link (MARVEL) domain, claudins, and Ig superfamily proteins (e.g., junctional adhesion molecules [JAM] and coxsackievirus B adenovirus receptor [CAR]) [8]. Peripheral TJ proteins include F-actin, F-actin-binding scaffold proteins, non-F-actin-binding scaffold proteins, and cell polarity and signaling molecules. The zonula occludens (ZO) proteins are the major peripheral membrane proteins. Transmembrane proteins of the TJs bind to peripheral membrane TJ proteins via their intracellular domains and organize the cellular signal transduction and cellular responses. The ZO proteins as part of TJs connect with the AJs and cytoskeleton composed of actin [9].
While we have mainly focused on TJs, AJs are positioned immediately below the TJs in the cells. Both TJ and AJ proteins provide polarity and help maintain intercellular adhesion. The AJ proteins consist of two basic units: the nectin–afadin complex and the classical cadherin-catenin complex. Nectin is an immunoglobulin-like intercellular adhesion molecule, and afadin is a nectin- and actin-filament binding protein that connects nectin to the actin cytoskeleton. The nectin adhesion system organizes E-cadherin-based AJs and claudin-based TJs in epithelial cells [10]. E-cadherin contains an extracellular domain that forms homotypic, calcium-dependent adhesions between epithelial cells. It is associated with the actin cytoskeleton through catenins. The actin microtubule cytoskeleton, a dynamic structure, maintains the cell shape and enables cilia motion, vesicle transport, and cell proliferation [11]. At the basolateral side of E-cadherin-mediated cell–cell contacts, the desmosomes, consisting of nonclassical cadherins, are formed, providing mechanical strength to the tissues. Gap junctions, or membrane channels, are formed between the neighboring cells through connexins, which allow the direct passage of ions, secondary messengers, and metabolites [12]. The AJs are critical for cell–cell contact at the basolateral surface, and the TJ proteins play an important role in relaying the molecular signal to its intracellular molecular partners from the periphery of the cells.
GENETIC MOUSE MODELS OF TJ PROTEINS
Investigations in genetic mouse models have highlighted the importance of different TJ proteins in maintaining epithelial polarity and barrier function. Knockdown of individual claudins in mice revealed mild lung phenotypes, suggesting that the other proteins in the lung can compensate for the loss of claudin function to some extent; the claudin-4 and claudin-18 knockout mice demonstrated increased solute permeability and alveolar fluid clearance [13,14,15,16,17]. JAM-A-deficient mice demonstrated increased susceptibility to pulmonary edema against lipopolysaccharide (LPS) challenge, which correlates with a transient disruption of claudin-18, ZO-1, and ZO-2 localizations to TJs in the lung and a delay in upregulation of claudin-4 [18]. A mouse model with conditional loss of E-cadherin in lung epithelial cells showed normal lung development at the time of birth, but progressive epithelial damage in adulthood, as evidenced by airway epithelial denudation, decreased ZO-1 expression, loss of ciliated cells, and enlarged alveolar spaces [19]. An afadin knockdown attenuates the interaction between ZO-1 and p120-catenin proteins [20]. Targeted disruption of either ZO-1 or ZO-2 in mice results in embryonic death that correlates with disruption of the paracellular barrier and the structure of cell junctions. The ZO-1 gene-deletion is associated with a defective organization of notochord, neural tube, and allantois and is embryonically lethal in mice at E10.5 to E11.5 [21]. Similarly, ZO-2-deleted mice do not survive beyond the embryo stage due to compromised TJ structure and function [22]. In contrast to the ZO-1 and ZO-2 null phenotypes, mice and cell systems with the ZO-3 gene deletion express no abnormalities. These observations suggest the dispensable function of ZO-3 [23]. Occludin knockout mice are viable with no morphological effect on TJs or intestinal barrier function. However, histological abnormalities are observed in different tissues: chronic inflammation and hyperplasia of gastric epithelium, testicular atrophy, salivary gland dysfunction, thinning of compact bone, and brain calcifications. The occludin deficiency in genetic mice does not affect the expression or localization of claudin-3 or claudin-1 in the intestinal epithelial cells [24, 25]. The phenotype of occludin-deficient mice has been linked by relocalization of tricellulin from tricellular to bicellular junctions [26, 27]. The double knockout of the occludin and tricellulin genes reduces the strand-to-strand junction points of the TJ strands, whereas loss of either occludin or tricellulin has no drastic effects. The MarvelD3 could also have a redundant role with tricellulin and occludin. Claudin-18 deficiency results in alveolar barrier dysfunction and impaired alveologenesis [13, 15]. Impaired TJ structure and/or function have also been reported in mice deficient in lymphoblastic leukemia-derived sequence (Lyl)-1, Crumbs (Crb3), and sirtuins (SIRTs) [28,29,30].
TJ PROTEINS AND MEMBRANE PERMEABILITY IN LUNG INJURY
Lung injuries manifested as non-cardiogenic pulmonary edema, respiratory distress, and hypoxemia result from various types of stimuli that directly or indirectly injure the lung. Lung injuries associated with acute respiratory distress syndrome (ARDS) are characterized by exposure to a known risk factor or worsening of the respiratory symptoms within 1 week, bilateral opacities on chest imaging (radiological assessment), edema, and oxygenation status indicated by the ratio of arterial oxygen partial pressure (PaO2 in mmHg) to fractional inspired oxygen (FiO2 expressed as a fraction; physiological criteria) [31]. A pro-inflammatory increase in vascular permeability and neutrophil infiltration, lung edema, and widespread damage to lung cells, biochemical components, structures, and alveolar barrier are hallmarks of lung injury [31, 32].
The airway epithelium acts as a physical barrier to prevent the entry of potential pathogens or noxious environmental stimulants across the airway mucosa [33]. Damage or dysfunction of the TJs results the deterioration of the epithelial cell function, increased permeability, and lung edema. Alteration of the TJs facilitates the passage of infectious agents, exogenous toxins and endogenous products into the systemic circulation, contributing to ARDS and multi-organ failure [34]. For the purposes of this review, we performed a PubMed search (2000–2021) using a combination of keywords (lung injury and tight junction; lung injury and membrane permeability; lung inflammation and membrane permeability; ARDS and tight junction; ARDS and membrane permeability). The association of altered expression and localization of TJ proteins with various lung conditions is summarized in the Supplemental Table.
TJ ASSEMBLY AND FUNCTION
The TJs are heavily cross-linked structures and are dynamic in nature, presenting challenges for detailed investigations at molecular and cellular levels [35]. The pharmacological modulators, genetically modified cells, and animal models have facilitated studies on the TJs. The transmembrane TJ proteins (e.g., claudins and occludin) form strands between neighboring cells. These proteins connect with the actin-myosin cytoskeleton through their interaction with scaffolding protein, mainly ZOs [36]. Despite a great understanding of many TJ proteins, the components of the selectively permeable barrier are not clearly known. Rapid freezing of the newly formed TJ barrier indicated cylinder-like structures, which were interpreted as inverted phospholipid micelles [37]. Additional pieces of evidence for barrier loss after cholesterol depletion [38] and interaction of occludin with lipid raft component caveolin-1 [39,40,41] suggest the role of membrane lipids in TJ formation.
TJ assembly and function are known to be controlled by the Ras homolog (Rho)GTPase. The activation of RhoGTPase is regulated by GDP to GTP nucleotide exchange factors and by GTP hydrolysis. The RhoGTPase stimulates specific effectors known as Rho kinases (ROCKs). The ROCKs phosphorylate and activate myosin light chain II (MLC) [42, 43] via two mechanisms, direct phosphorylation of MLC and indirect phosphorylation of the regulatory subunit of MLC phosphatase (MYPT1), which suppress MLC phosphatase activity [44]. The ATP-dependent ratcheting of actin and myosin is catalyzed by the calcium calmodulin-dependent non-muscle MLC kinase (MLCK) [45]. Several TJ proteins directly interact with actin and myosin, providing stability for the TJ complex.
The RhoGTPase/ROCK signaling participates in both assembly and disruption of TJs [46, 47]. The disruption or opening of TJs as a result of infections, inflammation, and toxic stimuli involves the phosphorylation of MLC2 and contraction of the actomyosin ring. Additional signaling molecules include mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinases (ERK1/2), mechanistic target of rapamycin (mTOR), caveolin-1, intracellular Ca2+-dependent mechanism, G protein, protein kinase C, phosphoinositol 3 kinase (PI3K), protein phosphatases, phosphorylation-related regulation, and small GTPases, depending on the tissue microenvironment [48,49,50,51,52,53].
TJ DISRUPTION DURING LUNG INJURY AGAINST INFECTIOUS AND INFLAMMATORY STIMULI
Normally, the lower airways are sterile, free from bacteria or inflammatory cells, and well protected by several layers of defenses, including antimicrobial peptides and mucins. Significant changes have been identified in TJ proteins in lung cell systems, animal models, and human patients suffering from lung injury, inflammation, and ARDS. Alterations in TJs are often characterized by reduced TJ strand formation, strand breaks, and altered TJ protein expression and distribution. Pulmonary insults with environmental stimulants and pathogens initiate the injury at the alveolar side of the alveolar-capillary barrier. Many studies have focused on the capillary endothelial barrier; little has been investigated about the barrier function of the alveolar epithelium. Mechanical stretch [54]; viruses, such as SARS-CoV-2, and bacterial pathogens [55,56,57,58]; pathogen-associated molecular patterns (PAMPs, e.g., LPS) [18]; inflammatory cytokines, such as interleukin (IL)-4, IL-13, tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ); and reactive oxygen species [59] are known to disrupt TJ assembly at the epithelial side of the barrier. We describe the current understanding on the cellular and molecular mechanisms of TJ disruption mainly at the level of alveolar epithelial cells during lung injury and inflammation. Type I and type II alveolar epithelial cells differ in their morphology and function, including the expression of the claudins [12, 60].
The mechanical stretch mimicking the ventilation-induced lung injury increases the phosphorylation of protein kinase RNA-like endoplasmic reticulum kinase (p-PERK) and integrated stress response (ISR) marked by eukaryotic initiation factor-2alpha (p-ELF2alpha), activating transcription factor-4 (ATF-4), and CCAAT/enhancer-binding protein homologous protein (CHOP), eventually resulting in permeability changes in primary alveolar type 1-like epithelial cells [61]. The cyclic stretches (20%) activated cSrc, induces degradation of E-cadherin, p120, and occludin in the mouse lung epithelial cell system [62]. The alveolar epithelial cells stretch leads to an increase in protein kinase B or Akt and LIM kinase and decrease in cofilin phosphorylation, suggesting involvement of the Ras-related C3 botulinum toxin substrate (Rac1)/Akt pathway [63].
The TJs and lung epithelial barrier are directly affected by pathogens or PAMPs: tyrosine kinase BceF and the phosphotyrosine phosphatase BceD Burkholderia contaminans [64], Pseudomonas aeruginosa [65,66,67], Stenotrophomonas maltophilia protease, Bacillus anthracis [68], and viruses (respiratory syncytial virus [RSV], rhinovirus, coxsackievirus, adenovirus, influenza, SARS-CoV-2, papillomavirus, and vaccinia virus) [69,70,71]. Pore-forming toxins released from bacteria induce necroptosis in lung epithelial cells as a result of ion dysregulation arising from membrane permeabilization [72].
The cytokines deregulate epithelial sodium channel (ENaC) activity, which results in fluid accumulation and alveolar flood, loss of normal gas exchange, and hypoxemia [73]. Among various cytokines, TNF-α and IL-1β increase pulmonary epithelial permeability [74,75,76]. TNF-α has been shown to alter the expression and distribution of TJ proteins (ZO-1, claudin-2, claudin-4, and claudin-5) and β-catenin [77], remodel actin for the formation of contractile stress fibers [78], and disrupt epithelial barrier function [79]. The TNF-α induces ceramide levels in lung epithelial cells, which leads to generation of sphingosine. Sphingosine is rapidly phosphorylated to sphingosine-1-phosphate (S1P), which activates RhoGTPase and ROCK and helps control the barrier integrity in endothelial cells [80]. An accumulation of ceramide decreases the barrier function of alveolar type II epithelial cells [81]. The ceramide and sphingomyelin metabolites are also known to suppress surfactant phosphatidylcholine synthesis in lung epithelial cells via protein kinase C (PKC)-α, p38 MAPK, cytosolic phospholipase A2 (cPLA2), and 5-lipoxygenase [82, 83]. In human airway epithelial cells, inhibition of the src-kinase attenuates TNF-α-induced TJ disruption and partly restores the TJ [84]. The inflammatory changes and lung TJ function are subdued by treatment with Etanercept, a TNF-α soluble receptor antagonist [77, 85]. The IL-1β activates transforming growth factor (TGF)-β through RhoA/αβ6 integrin-dependent mechanisms. Inhibition of the αβ6 integrin and/or TGF-β signaling suppresses the IL-1β-mediated protein permeability across alveolar epithelial cell monolayer [86]. ZO-1 and occludin expression and lung epithelial barrier function are also reduced by IL-4 and IL-13, but are enhanced by IFN-γ [87]. Prostaglandin E2 production is associated with p38 and c-jun N-terminal kinase, cPLA2, cyclooxygenase (COX)-2 mRNA, and disruption of the membrane barrier in human alveolar epithelial cells [88]. Pro-inflammatory thrombin and histamine modulate RhoGTPase-ROCK-MLCK and actomyosin contraction in endothelial cells through PKC (reviewed in [89]).
The damage-associated molecular patterns (DAMPs), such as hyaluronic acid binding protein-2 (HABP2), released during injury negatively regulate the vascular integrity via activation of protease-activated receptor (PAR)/RhoA/ ROCK signaling [90]. The mitochondrial DAMPs, such as fragmented mitochondria, induce MAPK phosphorylation in endothelial cells, which increases polymorphonuclear leukocytes (PMN) adherence and membrane permeability. The endosomal TLR inhibitor chloroquine has been shown to inhibit the permeability changes in endothelial cells [91].
It is now well recognized that TNF-α downregulates epithelial barrier function via activating nuclear factor (NF)-κB. NF-κB can directly modulate the TJ permeability [92]. The activation of NF-κB leads to the release of other inflammatory mediators, such as IL-6 and IL-1β, which have been shown to increase the airway permeability [93, 94].
Two pathways have been proposed for the paracellular movement of molecules. The claudin-containing “pore” controls the movement of ions in a charge- and size-selective manner, and the “leak” pathway allows limited movement of large macromolecules [95, 96]. The cell signaling at TJs is bidirectional, such that signals are transmitted from the cell interior to TJs and vice versa. For example, the claudins form the paracellular cation and water permeable channels for transport of solutes and ions in both directions and affect cell proliferation and migration [97].
The expression of claudin-4 and claudin-18 is regulated in an opposite manner during lung injury. An increase in claudin-4, but a decrease in claudin-18, is observed during injury (reviewed in [96]). Data show that the PKC activation increases claudin-4 expression in primary rat and human lung epithelial cells, and jun N-terminal kinase (JNK) inhibition blocks this increase in claudin-4. Findings from experimental and human lung studies suggest that claudin-4 supports the repair of epithelial barrier [96]. During the repair phase, the hepatocyte growth factor (HGF) protects the pulmonary endothelial cell cytoskeleton via Rho- and Rac-specific nucleotide exchange factor Tiam 1/Rac-GTPase-mediated pathways [98, 128]. The LPS secreted by Gram-negative bacteria is the most potent ligand for TLR4. A number of other PAMPs, including SARS-CoV-2 viral protein, and DAMPs released during inflammation and injury are also sensed by TLR4. High mobility group box 1 protein (HMGB1) release also induces TLR4 and PKC-mediated internalization of surface TJs in the pulmonary epithelium [129]. The alarmins S100A8/A9 promote lung injury through activation of alveolar epithelial cells in a TLR4-dependent manner [130]. After the recognition of PAMPs and DAMPs, activated TLR4 induces a complex network of intracellular signaling pathways, including association with its intracellular co-receptor molecules (myeloid differentiation primary response 88 [MYD88] and toll-interleukin 1 receptor [TIR] domain containing adaptor protein inducing IFN-β [TRIF]), stimulation of nuclear factor (NF)-κB, activator protein (AP)-1, and interferon-regulatory factor (IRF) transcription factors, PI3K/Akt/mTOR and PKC pathways, and priming of inflammasome for persistent inflammatory response (Fig. 1). LPS stimulates mTOR phosphorylation and decreases microtubule-associated protein-1 light chain 3 beta (MAP1LC3B/LC3B)-II, a marker of autophagy, in mouse lung epithelium and human bronchial epithelial cells. The activation of mTOR is mediated by TLR4 signaling. Specific knockdown of mTOR in epithelial cells in mice attenuates barrier disruption [50]. The co-culture of mesenchymal stem cells reduces inflammation in LPS-stimulated alveolar epithelial cells via modulation of the TLR4-signaling pathway by an enhanced secretion of KGF and angiopoietin [131].
Illustration of activated TLR4 signaling by recognition of pathogen- and damage-associated molecular patterns (PAMPs and DAMPs) present in the extracellular milieu and organization of TJ proteins at the apical surface of epithelial cells. While the expression and activity of TLR4 are increased, the disruption of TJ proteins and actin cytoskeleton leads to compromised barrier function during lung injury. An activated TLR4 forms a transmembrane complex upon binding to its ligand and is internalized in the cell. Hypothetically, the TLR4 complex may associate with TJs (A) or downstream TLR4-signaling and effector molecules (B) and affect the TJ assembly and compromise the epithelial barrier function. The circadian rhythm and yet unknown mechanisms could potentially regulate TLR4-signaling, TJ assembly, and barrier function. Intracellular co-receptors of TLR4-signaling pathway (MYD88, myeloid differentiation primary response 88, TIRAP, toll-interleukin 1 receptor [TIR] domain containing adaptor protein, TRAM, TRIF-related adaptor molecule, TRIF, TIR-domain-containing adaptor protein inducing interferon-β) are identified within the figure.
GENETIC AND PHARMACOLOGICAL MODULATION OF TLR4, PERMEABILITY, TIGHT JUNCTION INTEGRITY, AND LUNG INJURY
Studies using pharmacological modulators and agents, and investigations in genetic mouse models have suggested the role of TLR4 in permeability and lung injury. Significantly lower amounts of total protein were detected in bronchoalveolar lavage fluid (BALF) of the C3H/HeJ mice than in those of C3H/OuJ mice against exposure to ozone [122]. The TLR4 deficiency prevents the LPS-induced pulmonary injury [132]. The involvement of TLR4 in disruption of TJs is further emphasized by the neutralization of DAMPs, like HMGB1 [129], and blockade of TLR4 with synthetic compounds or natural products, such as catalpol [133], piceatannol [134], oxycodone [135], madecassoside [136], Houttuynia cordata polysaccharides [137], Schisandrin [138], Ma-**ng-Shi-Gan-Tang [139], Xuebi**g (XBJ) [140], and Sargassum horneri (Turner) [141]. Saquinavir, an inhibitor of HIV protease, also ameliorates the LPS-induced lung injury and permeability with lowered TLR4, but enhanced VE-cadherin [142]. Common observations relate with an increase in TLR4 expression and permeability and reduced expression or disrupted localization of TJ proteins in these lung injury models, which are reversed by these agents for a protective response. Some chemical components, such as Hippophae rhamnoides polysaccharide and selenium-enriched yeast, regulated the TLR4 and NF-κB and increased the expression of claudin-1, ZO-1, and occludin in intestinal injury models [143, 144]. Although the specificity of the modulation of TLR4 signaling is uncertain in the abovementioned studies with different chemical compounds and agents, the results suggest a link between TLR4 and increased permeability via TJ disruption during lung injury.
TREATMENT WITH CORTICOSTEROIDS
Treatment with corticosteroids is the mainstay for patients with lung injury conditions, including ARDS and asthma, despite inconsistent evidence of their efficacy with different clinical protocols. An improvement in patients’ condition has been reported in some studies. However, clinical data also show limited or no effect on patients’ outcomes, even at high treatment doses [145,146,147,148,149,150,151,152,153,154,155,156].
The anti-inflammatory effects of corticosteroids are recognized by the inhibition of leukocyte traffic and migration at the site of inflammation, perturbed cell functions, and suppression of the production of inflammatory molecules and mediators [157, 158]. Lipophilic synthetic corticosteroids easily cross the plasma membrane and bind to cytosolic glucocorticoid receptor, a member of the steroid hormone receptor family of ligand-inducible transcription factors. Upon binding to the ligand, the glucocorticoid receptor undergoes conformation change and translocates into the nucleus [159]. Interaction with glucocorticoid response elements in the nucleus increases the transcription of anti-inflammatory genes. A suppressed synthesis of pro-inflammatory proteins or transrepression results from competition for nuclear coactivators or direct or indirect interaction with transcription factors. Non-genomic pathways are equally important in mediating the effects of corticosteroids [160]. Treatment with corticosteroids affects the expression of TLR4 and IL-8 [161], but upregulates the expression of claudin-8 and decreases the paracellular permeability in a lung epithelial cell culture model of lung injury [162].
ROLE OF TLR4 IN RESISTANCE TO CORTICOSTEROID TREATMENT
As mentioned above, many patients do not respond to corticosteroid treatment. Several mechanisms may exist for steroid resistance, and these may differ in patients who are non-responsive to corticosteroid treatment [151]. Increased expression of the non-responsive beta isoform of glucocorticoid receptor, activation of p38 MAPK leading to phosphorylation of glucocorticoid receptors and reduced corticosteroid binding affinity within nucleus, excessive activation of the JNK pathway, reduced suppression or no effect of corticosteroid on cytokine release, impaired nuclear localization of glucocorticoid receptors, and defective histone acetylation are some of the plausible reasons for steroid-resistance [163,164,165,166]. One report has also identified that the circadian clock gene disruption corroborates with the loss of efficacy of synthetic dexamethasone [114]. Recent reports suggest that steroid resistance is strongly associated with activation of innate immune responses elicited by TLR2, TLR4, and NLRP3 inflammasomes [167, 168]. As such, the corticosteroids significantly compromise the bactericidal mechanisms in alveolar macrophages and in a mouse model of pneumococcal pneumonia [169]. Treatment with corticosteroids is associated with an increased risk of community-acquired pneumonia in patients with COPD [170, 171]. Patients with corticosteroid-resistant asthma demonstrate airway expansion of specific Gram-negative bacteria, which trigger MYD88-dependent transforming growth factor-β-associated kinase-1 activation, resulting in p38 MAPK phosphorylation, NF-κB activation, and transcription of pro-inflammatory cytokines [172]. Repeated exposure to LPS has been shown to activate PI3K, resulting in decreased levels of Histone deacetylase-2 and NF-E2-related factor 2 (Nrf2) and corticosteroid-insensitive airway inflammation [173]. Furthermore, sensitization with LPS in combination with β-glucan (fungal ligand) synergistically promotes corticosteroid refractory neutrophilic inflammation [174]. A cooperative signaling between interferon-γ and LPS-induced TLR4/MYD88 has also been shown to regulate macrophage-dependent, steroid-resistant inflammation [175, 176]. While the corticosteroids exert anti-inflammatory effects to some extent, the significance of unaltered NF-κB-DNA binding and activation and an increase in expression of the p65 component of NF-κB remains unknown [177].
TLR4, CIRCADIAN RHYTHM, AND DISRUPTION OF TJ PROTEINS IN THE LUNG
After recognition of its ligand, the TLR4 activates a complex network of intracellular signaling, resulting in activation of NF-κB, AP-1, and IRF3 transcription factors, PKCs, MAPKs, PI3K, and inflammatory cytokines and chemokines (Fig. 1). As described above and in Table 2, TLR4 activation and decreased expression and/or localization of TJ proteins are unequivocally noted during lung injury. An increased expression and activity of the aggravating downstream molecules, cytokines and chemokines, PAMPs, and DAMPs are evident in tissues and fluids of animal models and patients with lung injury. However, there is little information regarding whether an activated TLR4 forming a transmembrane complex with its co-receptor molecules can directly interact with TJs or whether the downstream TLR4-signaling molecules can affect the expression, assembly, and localization of TJs in lung epithelial cells. The circadian regulation of TLR4 signaling and organization of TJ proteins remains to be studied in lung cell systems and disease models. A thorough understanding of molecular events, signaling, and networks within different lung compartments and cells can facilitate development of novel therapies for restoration of the lung barrier, function and homeostasis, and control of severe outcomes in patients with lung inflammatory and injury conditions.
AVAILABILITY OF DATA AND MATERIALS
Not applicable.
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We thank Kathy Kyler, Staff Editor at the OUHSC for her editorial help.
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This work was supported by the funding from National Heart, Lung, and Blood Institute of the National Institute of Health under award number R01 HL136325. Dr. Nachiket M. Godbole’s (postdoctoral fellow) stipend was supported through the American Association of Immunologists Careers in Immunology Fellowship Program.
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Godbole, N.M., Chowdhury, A.A., Chataut, N. et al. Tight Junctions, the Epithelial Barrier, and Toll-like Receptor-4 During Lung Injury. Inflammation 45, 2142–2162 (2022). https://doi.org/10.1007/s10753-022-01708-y
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DOI: https://doi.org/10.1007/s10753-022-01708-y