Homeostatic cross-talk between host inflammation and the barrier framework is essential to maintaining barrier integrity at mucosal surfaces in the lung. However, a dysregulated or overly amplified host response often results in damage-associated structural changes to the barrier, leading to altered epithelial and/or endothelial cell phenotypes during acute or chronic inflammatory conditions. For instance, influenza infection recruits CCR2hi inflammatory monocytes (IMs), which interact with alveolar epithelial cells in the lung. The cross-talk involves the physical interactions between IMs and alveolar epithelia, as well as the inflammatory cytokine-mediated induction of epithelial response in the lungs. These immune events promote the dysregulation of epithelial tight junction (TJs) proteins, cilia function, mucus production, and cell differentiation, leading to an increased susceptibility to bacterial diseases in influenza-infected hosts. Due to enormous antigenic variation in the influenza virus, the host memory T cell response is of limited significance, and the role of monocyte-mediated epithelial damage serves a key element of therapeutic intervention.
A dominant Th2 phenotype characterizes the chronic lung inflammation arising from allergic asthma. Epithelial IL-33 response promotes the recruitment of allergen-specific Th2 cells producing signature cytokines, IL-4, IL-5, and IL-13. Additionally, an emerging role of innate lymphoid cells 2 (ILC2S) and Th9 cells has been noted in asthma pathophysiology. Th2 cytokines play a crucial role in the recruiting of eosinophils to the airway. In asthma, acute inflammatory-epithelial cross-talk manifests at two levels: (1) IL-4, IL-5 and IL-13 cytokine-mediated induction of epithelial response, and (2) eosinophil-epithelial cross-talk. These immune interactions result in epithelial changes such as dysregulation of TJs, epithelial leaking, goblet hyperplasia, and sub-epithelial fibrosis. Clinically, there exists significant overlap in asthma and COPD phenotypes. Smoke-related changes in lung physiology can exacerbate asthma pathology or vice-versa.
A significant knowledge gap exists in our understanding of key signaling pathways in lung alveolar epithelia involved in the loss of barrier integrity during acute and chronic inflammatory conditions. A better understanding of these interactions will lead to the development of novel therapies that are better able to combat changes associated with causing dysregulation of barrier integrity at lung mucosal surfaces.
Therefore, the goal of this Research Topic is to outline the most notable and current understandings of the cross-talk between immune cells involved in acute and chronic inflammation with that of barrier framework in the lung, leading to the susceptibility for infections and the development of the chronic inflammatory disorders.
We welcome the submission of Review, Mini-Review and Original Research articles covering, but not limited to, the following topics:
1. The consequences of acute and chronic inflammation for the susceptibility of bacterial and viral infections in the lung.
2. The consequence of the cross-talk between immune cells involved in acute/chronic inflammation and the barrier framework on lung pathology.
3. The damage-response framework in the lung: how to better define the endpoints of beneficial and pathological inflammation in pulmonary infection and inflammatory diseases.
Homeostatic cross-talk between host inflammation and the barrier framework is essential to maintaining barrier integrity at mucosal surfaces in the lung. However, a dysregulated or overly amplified host response often results in damage-associated structural changes to the barrier, leading to altered epithelial and/or endothelial cell phenotypes during acute or chronic inflammatory conditions. For instance, influenza infection recruits CCR2hi inflammatory monocytes (IMs), which interact with alveolar epithelial cells in the lung. The cross-talk involves the physical interactions between IMs and alveolar epithelia, as well as the inflammatory cytokine-mediated induction of epithelial response in the lungs. These immune events promote the dysregulation of epithelial tight junction (TJs) proteins, cilia function, mucus production, and cell differentiation, leading to an increased susceptibility to bacterial diseases in influenza-infected hosts. Due to enormous antigenic variation in the influenza virus, the host memory T cell response is of limited significance, and the role of monocyte-mediated epithelial damage serves a key element of therapeutic intervention.
A dominant Th2 phenotype characterizes the chronic lung inflammation arising from allergic asthma. Epithelial IL-33 response promotes the recruitment of allergen-specific Th2 cells producing signature cytokines, IL-4, IL-5, and IL-13. Additionally, an emerging role of innate lymphoid cells 2 (ILC2S) and Th9 cells has been noted in asthma pathophysiology. Th2 cytokines play a crucial role in the recruiting of eosinophils to the airway. In asthma, acute inflammatory-epithelial cross-talk manifests at two levels: (1) IL-4, IL-5 and IL-13 cytokine-mediated induction of epithelial response, and (2) eosinophil-epithelial cross-talk. These immune interactions result in epithelial changes such as dysregulation of TJs, epithelial leaking, goblet hyperplasia, and sub-epithelial fibrosis. Clinically, there exists significant overlap in asthma and COPD phenotypes. Smoke-related changes in lung physiology can exacerbate asthma pathology or vice-versa.
A significant knowledge gap exists in our understanding of key signaling pathways in lung alveolar epithelia involved in the loss of barrier integrity during acute and chronic inflammatory conditions. A better understanding of these interactions will lead to the development of novel therapies that are better able to combat changes associated with causing dysregulation of barrier integrity at lung mucosal surfaces.
Therefore, the goal of this Research Topic is to outline the most notable and current understandings of the cross-talk between immune cells involved in acute and chronic inflammation with that of barrier framework in the lung, leading to the susceptibility for infections and the development of the chronic inflammatory disorders.
We welcome the submission of Review, Mini-Review and Original Research articles covering, but not limited to, the following topics:
1. The consequences of acute and chronic inflammation for the susceptibility of bacterial and viral infections in the lung.
2. The consequence of the cross-talk between immune cells involved in acute/chronic inflammation and the barrier framework on lung pathology.
3. The damage-response framework in the lung: how to better define the endpoints of beneficial and pathological inflammation in pulmonary infection and inflammatory diseases.
![Overview of the bacterial pneumonia-associated innate immune response responsible for ALI. (A) Gram-negative bacterial pneumonia and ALI. The PRRs [TLRs (TLR4) and Inflammasome proteins (NLRP3)] expressed on the pulmonary innate immune cells (AECs, BECs, AMs, DCs, and NK cells) recognize Gram-negative bacteria in the lungs. This recognition induces pro-inflammatory cytokine (TNF-α, IL-6, IL-8, and IL-1β) and chemokine release. Chemokines and pro-inflammatory cytokines induce the neutrophil infiltration in the alveoli from the pulmonary blood capillaries through their vascular endothelium via diapedesis. The infiltrated neutrophils help in the pathogen clearance but also cause bystander inflammatory pulmonary tissue damage via damaging PECs or AECs. In the severe pneumonia-associated ALI, the vascular leakage of proteins and erythrocytes also occurs in the lungs. The pulmonary NK cells also release IFN-γ, which further enhances neutrophil infiltration and ALI. However, the increase in ILC3s at later stages increases the IL-17 level. This cytokine helps in the increased phagocytosis of the pathogen and the resolution of the Gram-negative bacterial pneumonia-induced ALI. (B) Gram-positive bacterial pneumonia-associated ALI. The recognition of the Gram-positive bacteria (S. aureus) induces the increased the production of chemokines and pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, and IL-8), which via binding to the corresponding receptors (CXCR2) on the neutrophils induce their diapedesis to the lung alveoli from the pulmonary vascular endothelium. Neutrophils, along with bacterial clearance, also cause ALI. Pulmonary vascular endothelium damage also causes vascular leakage. The Pulmonary NK cells via their NCR1 interact with AMs to further increase the pro-inflammatory cytokine release, which further aggravates the neutrophil infiltration, pathogen clearance, and ALI also. The NLRP3 also works independently of inflammasome activation via inducing the release of TFF2 and ITLN-1. TFF2 inhibits ALI and helps in its resolution, whereas ITLN-1 clears the infection via increasing the pathogen phagocytosis. The CCL20 released from AECs increases the pulmonary ILC3 numbers, which release IL-22 that inhibits ALI and helps in its resolution.](https://www.frontiersin.org/_rtmag/_next/image?url=https%3A%2F%2Fwww.frontiersin.org%2Ffiles%2FArticles%2F524923%2Ffimmu-11-01722-HTML%2Fimage_m%2Ffimmu-11-01722-g002.jpg&w=3840&q=75)
