Abstract
Fibrosis is a life-threatening disorder caused by excessive formation of connective tissue that can affect several critical organs. Innate immune cells are involved in the development of various disorders, including lung fibrosis. To date, several hematopoietic cell types have been implicated in fibrosis, including pro-fibrotic monocytes like fibrocytes and segregated-nucleus-containing atypical monocytes (SatMs), but the precise cellular and molecular mechanisms underlying its development remain unclear. Repetitive injury and subsequent cell death response are triggering events for lung fibrosis development. Crosstalk between lung structured and non-structured cells is known to regulate the key molecular event. We recently reported that RNA-binding motif protein 7 (RBM7) expression is highly upregulated in the fibrotic lung and plays fundamental roles in fibrosis development. RBM7 regulates nuclear degradation of NEAT1 non-coding RNA, resulting in sustained apoptosis in the lung epithelium and fibrosis. Apoptotic epithelial cells produce CXCL12, which leads to the recruitment of pro-fibrotic monocytes. Apoptosis is also the main source of autoantigens. Recent studies have revealed important functions for natural autoantibodies that react with specific sets of self-antigens and are unique to individual diseases. Here, we review recent insights into lung fibrosis development in association with crosstalk between structured cells like lung epithelial cells and non-structured cells like migrating immune cells, and discuss their relevance to acquired immunity through natural autoantibody production.
Highlights
Fibrosis is a chronic progressive disorder that causes severe damage to several critical organs and can lead to life-threatening tissue dysfunction through excessive deposition of the extracellular matrix (ECM)
We found that RNA-binding motif protein 7 (RBM7) in lung structured cells is selectively elevated in the fibrotic phase and critical for fibrosis development, and uncovered an unprecedented role of sustained cell death of lung structured cells in the fibrotic phase regulated by RBM7 via nuclear degradation of
In our previous study [8], we found that apoptotic lung structured cells, such as cleaved caspase 3-positive lung epithelial cells, produce large amounts of the chemokine CXCL12, which is required for the recruitment of non-structured immune cells like pro-fibrotic monocytes, i.e., fibrocytes and segregated-nucleus-containing atypical monocytes (SatMs)
Summary
Fibrosis is a chronic progressive disorder that causes severe damage to several critical organs and can lead to life-threatening tissue dysfunction through excessive deposition of the extracellular matrix (ECM). This randomized, double-blind, placebo-controlled trial found that mortality and risk of hospitalization were increased in patients treated with the potent anti-inflammatory regimen compared with the placebo, suggesting that inflammation may not be an essential component of fibrosis development in IPF These observations challenge the hypothesis that inflammation itself drives fibrogenesis, and research interests have shifted toward the identification of other essential processes that can lead to lung fibrosis [4,6]. CXCL12, which leads to the recruitment of pro-fibrotic monocytes, i.e., segregated-nucleus-containing atypical monocytes (SatMs), resulting in the initiation of fibrosis Taken together, these results suggest that close interactions between structured cells like lung epithelial cells and non-structured cells like migrated immune cells are critical for myofibroblastdifferentiation/activation leading to fibrosis development. Apoptosis is the major source of autoantigens for natural autoantibodies, which can reflect the ongoing disease pathology and modify the disease course
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