Abstract
Interactions between the lung epithelium and the immune system involve a tight regulation to prevent inappropriate reactions and have been connected to several pulmonary diseases. Although the distal lung epithelium and local immunity have been implicated in the pathogenesis and disease course of idiopathic pulmonary fibrosis (IPF), consequences of their abnormal interplay remain less well known. Recent data suggests a two-way process, as illustrated by the influence of epithelial-derived periplakin on the immune landscape or the effect of macrophage-derived IL-17B on epithelial cells. Additionally, damage associated molecular patterns (DAMPs), released by damaged or dying (epithelial) cells, are augmented in IPF. Next to “sterile inflammation”, pathogen-associated molecular patterns (PAMPs) are increased in IPF and have been linked with lung fibrosis, while outer membrane vesicles from bacteria are able to influence epithelial-macrophage crosstalk. Finally, the advent of high-throughput technologies such as microbiome-sequencing has allowed for the identification of a disease-specific microbial environment. In this review, we propose to discuss how the interplays between the altered distal airway and alveolar epithelium, the lung microbiome and immune cells may shape a pro-fibrotic environment. More specifically, it will highlight DAMPs-PAMPs pathways and the specificities of the IPF lung microbiome while discussing recent elements suggesting abnormal mucosal immunity in pulmonary fibrosis.
Highlights
The role of the immune system in the development and disease course of idiopathic pulmonary fibrosis (IPF) has been a matter of heated debate over the last decades
Molecular Patterns (PAMPs), such as lipopolysaccharides, ds/ ssRNA or unmethylated CpG DNA [87]. Both damage associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs) downstream signaling is mediated through Pattern Recognition Receptors (PRR), intracytoplasmic and membrane receptors consisting of 4 classes, Toll-Like Receptors (TLR), NOD-Like Receptors (NLR), C-type Lectin Receptors (CLR) and RIG-I-Like receptors (RLR) [88]
Further implication comes from the observation that High Motility Group Box 1 (HMGB1), uric acid or extracellular ATP, all recognized DAMPs, are increased in both human broncho-alveolar lavage (BAL) as well as in vivo and in vitro experimental conditions [89,90,91,92,93]
Summary
The role of the immune system in the development and disease course of idiopathic pulmonary fibrosis (IPF) has been a matter of heated debate over the last decades. Initial observations of increased neutrophil counts in the broncho-alveolar lavage (BAL) [1, 2] alongside the histologic presence of neutrophils, lymphocytes and macrophages in the proximity of fibrotic areas [1] led to the hypothesis that IPF starts as an inflammatory alveolitis and progresses to alveolar septal fibrosis over time. These observations formed the basis for the use of immunosuppressive therapies, in particular corticosteroids, in IPF.
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