Lung epithelial cells interact with immune cells and bacteria to shape the microenvironment in tuberculosis

Thorax ◽  
2022 ◽  
pp. thoraxjnl-2021-217997
Author(s):  
Amy M de Waal ◽  
Pieter S Hiemstra ◽  
Tom HM Ottenhoff ◽  
Simone A Joosten ◽  
Anne M van der Does
Keyword(s):  
Epithelial Cells ◽  
Immune Cells ◽  
Lung Epithelial Cells ◽  
Lung Epithelium ◽  
Adaptive Immune ◽  
Adaptive Immune Cells ◽  
Essential Components ◽  
Lung Epithelial ◽  
Sense And Respond ◽  
Tuberculosis Disease

The lung epithelium has long been overlooked as a key player in tuberculosis disease. In addition to acting as a direct barrier to Mycobacterium tuberculosis (Mtb), epithelial cells (EC) of the airways and alveoli act as first responders during Mtb infections; they directly sense and respond to Mtb by producing mediators such as cytokines, chemokines and antimicrobials. Interactions of EC with innate and adaptive immune cells further shape the immune response against Mtb. These three essential components, epithelium, immune cells and Mtb, are rarely studied in conjunction, owing in part to difficulties in coculturing them. Recent advances in cell culture technologies offer the opportunity to model the lung microenvironment more closely. Herein, we discuss the interplay between lung EC, immune cells and Mtb and argue that modelling these interactions is of key importance to unravel early events during Mtb infection.

scholarly journals SARS-CoV-2 Isolates Show Impaired Replication in Human Immune Cells but Differential Ability to Replicate and Induce Innate Immunity in Lung Epithelial Cells

2021 ◽  
Author(s):  
Miao Jiang ◽  
Pekka Kolehmainen ◽  
Laura Kakkola ◽  
Sari Maljanen ◽  
Krister Melén ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Epithelial Cells ◽  
Immune Cells ◽  
Human Lung ◽  
Lung Epithelial Cells ◽  
Lung Epithelial ◽  
Rapid Spread ◽  
Human Immune ◽  
Differential Ability ◽  
Interferon Responses

With the rapid spread of the coronavirus disease 2019 (COVID-19) pandemic, information on the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and regulation of innate immunity in human immune cells and lung epithelial cells is needed. In the present study, we show that SARS-CoV-2 failed to productively infect human immune cells, but different isolates of SARS-CoV-2 showed differential ability to replicate and regulate innate interferon responses in human lung epithelial Calu-3 cells.

scholarly journals Activation of the mTORC1/PGC-1 axis promotes mitochondrial biogenesis and induces cellular senescence in the lung epithelium

2019 ◽  
Vol 316 (6) ◽  
pp. L1049-L1060 ◽  
Author(s):  
Ross Summer ◽  
Hoora Shaghaghi ◽  
DeLeila Schriner ◽  
Willy Roque ◽  
Dominic Sales ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Cellular Senescence ◽  
Mitochondrial Biogenesis ◽  
Lung Epithelial Cells ◽  
Chronic Obstructive ◽  
Protective Mechanism ◽  
Peroxisome Proliferator ◽  
Lung Epithelium ◽  
Peroxisome Proliferator Activated Receptor ◽  
Lung Epithelial

Cellular senescence is a biological process by which cells lose their capacity to proliferate yet remain metabolically active. Although originally considered a protective mechanism to limit the formation of cancer, it is now appreciated that cellular senescence also contributes to the development of disease, including common respiratory ailments such as chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. While many factors have been linked to the development of cellular senescence, mitochondrial dysfunction has emerged as an important causative factor. In this study, we uncovered that the mitochondrial biogenesis pathway driven by the mammalian target of rapamycin/peroxisome proliferator-activated receptor-γ complex 1α/β (mTOR/PGC-1α/β) axis is markedly upregulated in senescent lung epithelial cells. Using two different models, we show that activation of this pathway is associated with other features characteristic of enhanced mitochondrial biogenesis, including elevated number of mitochondrion per cell, increased oxidative phosphorylation, and augmented mitochondrial reactive oxygen species (ROS) production. Furthermore, we found that pharmacological inhibition of the mTORC1 complex with rapamycin not only restored mitochondrial homeostasis but also reduced cellular senescence to bleomycin in lung epithelial cells. Likewise, mitochondrial-specific antioxidant therapy also effectively inhibited mTORC1 activation in these cells while concomitantly reducing mitochondrial biogenesis and cellular senescence. In summary, this study provides a mechanistic link between mitochondrial biogenesis and cellular senescence in lung epithelium and suggests that strategies aimed at blocking the mTORC1/PGC-1α/β axis or reducing ROS-induced molecular damage could be effective in the treatment of senescence-associated lung diseases.

Mesenchymal maintenance of distal epithelial cell phenotype during late fetal lung development

2007 ◽  
Vol 292 (3) ◽  
pp. L725-L741 ◽  
Author(s):  
Julie Deimling ◽  
Kate Thompson ◽  
Irene Tseu ◽  
Jinxia Wang ◽  
Richard Keijzer ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Notch Pathway ◽  
Secretory Protein ◽  
Lung Epithelial Cells ◽  
Clara Cell ◽  
Cell Phenotype ◽  
Lung Epithelium ◽  
Morphological Pattern ◽  
Lung Epithelial ◽  
Distal Lung

Classical tissue recombination experiments have reported that at early gestation both tracheal and distal lung epithelium have the plasticity to respond to mesenchymal signals. Herein we examined the role of epithelial-mesenchymal interactions in maintaining epithelial differentiation at late (E19–E21, term = 22 days) fetal gestation in the rat. Isolated distal lung epithelial cells were recombined with mesenchymal cells from lung, skin, and intestine, and the homotypic or heterotypic recombinant cell aggregates were cultured for up to 5 days. Recombining lung epithelial cells with mesenchyme from various sources induced a morphological pattern that was specific to the type of inducing mesenchyme. In situ analysis of surfactant protein (SP)-C, SP-B, and Clara cell secretory protein (CCSP) expression, as well as SP-C and CCSP promoter transactivation experiments, revealed that distal lung epithelium requires lung mesenchyme to maintain the alveolar, but not bronchiolar, phenotype. Incubation of lung recombinants with an anti-FGF7 antibody resulted in a partial inhibition of mesenchyme-induced SP-C promoter transactivation. Immunoreactivity for Delta and Lunatic fringe, components of the Notch pathway that regulates cell differentiation, was downregulated in the heterotypic recombinants. In contrast, Hes1 mRNA expression was increased in these recombinants. Cumulatively, these results suggest that at late fetal gestation, distal lung epithelial cells are not fully committed to a specific phenotype and still have the plasticity to respond to various signals. Their alveolar phenotype is likely maintained by Notch/Notch ligand interactions and mesenchymal factors, including FGF7.

scholarly journals Macrophage-Mediated Inflammation and Disease: A Focus on the Lung

2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
Emily Gwyer Findlay ◽  
Tracy Hussell
Keyword(s):  
Extracellular Matrix ◽  
Particulate Matter ◽  
Gas Exchange ◽  
Epithelial Cells ◽  
Immune Cells ◽  
Inflammatory Mediators ◽  
Lung Epithelial Cells ◽  
Vast Array ◽  
Lung Epithelial ◽  
Suppressive Phenotype

The lung is exposed to a vast array of inhaled antigens, particulate matter, and pollution. Cells present in the airways must therefore be maintained in a generally suppressive phenotype so that excessive responses to nonserious irritants do not occur; these result in bystander damage to lung architecture, influx of immune cells to the airways, and consequent impairment of gas exchange. To this end, the resident cells of the lung, which are predominantly macrophages, are kept in a dampened state. However, on occasion the suppression fails and these macrophages overreact to antigenic challenge, resulting in release of inflammatory mediators, induction of death of lung epithelial cells, deposition of extracellular matrix, and development of immunopathology. In this paper, we discuss the mechanisms behind this macrophage-mediated pathology, in the context of a number of inflammatory pulmonary disorders.

scholarly journals SARS-CoV-2 activates lung epithelia cell proinflammatory signaling and leads to immune dysregulation in COVID-19 patients by single-cell sequencing

2020 ◽  
Author(s):  
Huarong Chen ◽  
Weixin Liu ◽  
Dabin Liu ◽  
Liuyang Zhao ◽  
Jun Yu
Keyword(s):  
Immune Response ◽  
Epithelial Cells ◽  
Nk Cells ◽  
Single Cell ◽  
Immune Cells ◽  
Cell Types ◽  
Lung Epithelial Cells ◽  
Healthy Controls ◽  
Inflammatory Signaling ◽  
Lung Epithelial

Objective: The outbreak of Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 infection has become a global health emergency. We aim to decipher SARS-CoV-2 infected cell types, the consequent host immune response and their interplay in the lung of COVID-19 patients. Design: We analyzed single-cell RNA sequencing (scRNA-seq) data of lung samples from 17 subjects (6 severe COVID-19 patients, 3 mild patients who recovered and 8 healthy controls). The expression of SARS-CoV-2 receptors (ACE2 and TMPRSS2) was examined among different cell types in the lung. The immune cells infiltration patterns, their gene expression profiles, and the interplay of immune cells and SARS-CoV-2 target cells were further investigated. Results: Compared to healthy controls, the overall ACE2 (receptor of SARS-CoV-2) expression was significantly higher in lung epithelial cells of COVID-19 patients, in particular in ciliated cell, club cell and basal cell. Comparative transcriptome analysis of these lung epithelial cells of COVID-19 patients and healthy controls identified that SARS-CoV-2 infection activated pro-inflammatory signaling including interferon pathway and cytokine signaling. Moreover, we identified dysregulation of immune response in patients with COVID-19. In severe COVID-19 patients, significantly higher neutrophil, but lower T and NK cells in lung were observed along with markedly increased cytokines (CCL2, CCL3, CCL4, CCL7, CCL3L1 and CCL4L2) compared with healthy controls as well as mild patients who recovered. The cytotoxic phenotypes were shown in lung T and NK cells of severe patients as evidenced by enhanced IFNγ, Granulysin, Granzyme B and Perforin expression. Moreover, SARS-CoV-2 infection altered the community interplay of lung epithelial cells and immune cells: the interaction between epithelial cells with macrophage, T and NK cell was stronger, but their interaction with neutrophils was lost in COVID-19 patients compared to healthy controls. Conclusions: SARS-CoV-2 infection activates pro-inflammatory signaling in lung epithelial cells expressing ACE2 and causes dysregulation of immune response to release more pro-inflammatory cytokines. Moreover, SARS-CoV-2 infection breaks the interplay of lung epithelial cells and immune cells.

scholarly journals The intestinal neuro-immune axis: crosstalk between neurons, immune cells, and microbes

2021 ◽  
Author(s):  
Amanda Jacobson ◽  
Daping Yang ◽  
Madeleine Vella ◽  
Isaac M. Chiu
Keyword(s):  
Gastrointestinal Tract ◽  
Epithelial Cells ◽  
Immune Cells ◽  
Inflammatory Diseases ◽  
Intestinal Epithelial ◽  
Adaptive Immune ◽  
Neuron Populations ◽  
Adaptive Immune Cells ◽  
Molecular Events ◽  
Inflammatory Bowel

AbstractThe gastrointestinal tract is densely innervated by a complex network of neurons that coordinate critical physiological functions. Here, we summarize recent studies investigating the crosstalk between gut-innervating neurons, resident immune cells, and epithelial cells at homeostasis and during infection, food allergy, and inflammatory bowel disease. We introduce the neuroanatomy of the gastrointestinal tract, detailing gut-extrinsic neuron populations from the spinal cord and brain stem, and neurons of the intrinsic enteric nervous system. We highlight the roles these neurons play in regulating the functions of innate immune cells, adaptive immune cells, and intestinal epithelial cells. We discuss the consequences of such signaling for mucosal immunity. Finally, we discuss how the intestinal microbiota is integrated into the neuro-immune axis by tuning neuronal and immune interactions. Understanding the molecular events governing the intestinal neuro-immune signaling axes will enhance our knowledge of physiology and may provide novel therapeutic targets to treat inflammatory diseases.

scholarly journals Induction of Fibrinogen Expression in the Lung Epithelium during Pneumocystis carinii Pneumonia

1998 ◽  
Vol 66 (9) ◽  
pp. 4431-4439 ◽  
Author(s):  
Patricia J. Simpson-Haidaris ◽  
Mary-Anne Courtney ◽  
Terry W. Wright ◽  
Rachel Goss ◽  
Allen Harmsen ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Immunoelectron Microscopy ◽  
Pneumocystis Carinii ◽  
The Body ◽  
Alveolar Epithelial Cells ◽  
Lung Epithelial Cells ◽  
Northern Hybridization ◽  
Lung Epithelium ◽  
Lung Epithelial

ABSTRACT Pneumocystis carinii is an important pulmonary pathogen responsible for morbidity and mortality in patients with AIDS. The acute-phase response (APR), the primary mechanism used by the body to restore homeostasis following infection, is characterized by increased levels of circulating fibrinogen (FBG). Although the liver is the primary site of increased FBG synthesis during the APR, we unexpectedly discovered that FBG is synthesized and secreted by lung alveolar epithelial cells in vitro during an inflammatory stimulus. Therefore, we sought to determine whether lung epithelial cells produce FBG in vivo using animal models of P. cariniipneumonia (PCP). Inflammation was noted by an influx of macrophages to P. carinii-infected alveoli. Northern hybridization revealed that γ-FBG mRNA increased two- to fivefold in P. carinii-infected lung tissue, while RNA in situ hybridization demonstrated increased levels of γ-FBG mRNA in the lung epithelium. Immunoelectron microscopy detected lung epithelial cell-specific production of FBG, suggesting induction of a localized inflammatory response resembling the APR. A systemic APR was confirmed by a two- to fivefold upregulation of the levels of hepatic γ-FBG mRNA in animals with PCP, resulting in a corresponding increase in levels of FBG in plasma. Furthermore, immunoelectron microscopy revealed the presence of FBG at the junction of cell membranes of trophic forms of P. carinii organisms aggregated along the alveolar epithelium. These results implicate FBG in the pathogenesis of PCP in a manner similar to that of the adhesive glycoproteins fibronectin and vitronectin, which are known to participate in intra-alveolar aggregation of organisms and adherence ofP. carinii to the lung epithelium.

scholarly journals Role of β-catenin-regulated CCN matricellular proteins in epithelial repair after inflammatory lung injury

2013 ◽  
Vol 304 (6) ◽  
pp. L415-L427 ◽  
Author(s):  
Rachel L. Zemans ◽  
Jazalle McClendon ◽  
Yael Aschner ◽  
Natalie Briones ◽  
Scott K. Young ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Target Genes ◽  
Lung Epithelial Cells ◽  
Human Neutrophils ◽  
Albumin Concentration ◽  
Lung Epithelium ◽  
Inflammatory Injury ◽  
Epithelial Repair ◽  
Lung Epithelial

Repair of the lung epithelium after injury is integral to the pathogenesis and outcomes of diverse inflammatory lung diseases. We previously reported that β-catenin signaling promotes epithelial repair after inflammatory injury, but the β-catenin target genes that mediate this effect are unknown. Herein, we examined which β-catenin transcriptional coactivators and target genes promote epithelial repair after inflammatory injury. Transmigration of human neutrophils across cultured monolayers of human lung epithelial cells resulted in a fall in transepithelial resistance and the formation of discrete areas of epithelial denudation (“microinjury”), which repaired via cell spreading by 96 h. In mice treated with intratracheal (i.t.) LPS or keratinocyte chemokine, neutrophil emigration was associated with increased permeability of the lung epithelium, as determined by increased bronchoalveolar lavage (BAL) fluid albumin concentration, which decreased over 3–6 days. Activation of β-catenin/p300-dependent gene expression using the compound ICG-001 accelerated epithelial repair in vitro and in murine models. Neutrophil transmigration induced epithelial expression of the β-catenin/p300 target genes Wnt-induced secreted protein (WISP) 1 and cysteine-rich (Cyr) 61, as determined by real-time PCR (qPCR) and immunostaining. Purified neutrophil elastase induced WISP1 upregulation in lung epithelial cells, as determined by qPCR. WISP1 expression increased in murine lungs after i.t. LPS, as determined by ELISA of the BAL fluid and qPCR of whole lung extracts. Finally, recombinant WISP1 and Cyr61 accelerated repair, and Cyr61-neutralizing antibodies delayed repair of the injured epithelium in vitro. We conclude that β-catenin/p300-dependent expression of WISP1 and Cyr61 is critical for epithelial repair and represents a potential therapeutic target to promote epithelial repair after inflammatory injury.

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