IL-8 mediates idiopathic pulmonary fibrosis mesenchymal progenitor cell fibrogenicity

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease, but the mechanisms driving progression remain incompletely defined. We previously reported that the IPF lung harbors fibrogenic mesenchymal progenitor cells (MPCs), which serve as a cell of origin for IPF fibroblasts. Proliferating IPF MPCs are located at the periphery of fibroblastic foci in an active cellular front at the interface between the myofibroblast-rich focus core and adjacent normal alveolar structures. Among a large set of genes that distinguish IPF MPCs from their control counterparts, we identified IL-8 as a candidate mediator of IPF MPC fibrogenicity and driver of fibrotic progression. IPF MPCs and their progeny displayed increased steady-state levels of IL-8 and its cognate receptor CXCR1 and secreted more IL-8 than did controls. IL-8 functioned in an autocrine manner promoting IPF MPC self-renewal and the proliferation and motility of IPF MPC progeny. Secreted IL-8 also functioned in a paracrine manner stimulating macrophage migration. Analysis of IPF lung tissue demonstrated codistribution of IPF MPCs with activated macrophages in the active cellular front of the fibroblastic focus. These findings indicate that IPF MPC-derived IL-8 is capable of expanding the mesenchymal cell population and recruiting activated macrophages cells to actively evolving fibrotic lesions.

Evaluation of IL8 pathway on the ocular surface: new insights in patients with ocular mucous membrane pemphigoid

“…The role of IL8 in the modulation of inflammation and scarring has been suggested in other cicatrizing systemic diseases. Specifically, it has been demonstrated that patients with idiopathic pulmonary fibrosis showed an increase of IL-8 protein and mRNA expression in the bronchoalveolar fluid and it is associated with fibrosis progression (Pantelidis et al 1997;Yang et al 2018).…”

“…It has been showed that IL8 plays a key role in stimulating fibrogenic inflammatory reaction through neutrophils recruitment(Murphy ; Yang et al. ). Since neutrophils’ infiltration has been observed in patients with oMMP associated with progression of conjunctival scarring, also in the absence of active inflammation (Williams et al.…”

“…Recently, it has been demonstrated that local and systemic levels of IL8 are increased in cicatrizing inflammatory conditions such as autoimmune glomerulonephritis (Tramma et al 2012), Stevens-Johnson syndrome (SJS) (Gurumurthy et al 2018), toxic epidermal necrolysis (TEN) (Paquet et al 2007) and idiopathic pulmonary fibrosis (Southcott et al 1995). It has been showed that IL8 plays a key role in stimulating fibrogenic inflammatory reaction through neutrophils recruitment (Murphy 1997;Yang et al 2018). Since neutrophils' infiltration has been observed in patients with oMMP associated with progression of conjunctival scarring, also in the absence of active inflammation (Williams et al 2016), a major role of this cytokine may be hypothesized also in oMMP.…”

PulmonDB: a curated lung disease gene expression database

“…To show that PulmonDB can be used to recapitulate previously reported knowledge regarding COPD and IPF biology, we performed a literature search and manually selected relevant genes for each disease. We selected 19 genes related to IPF (not necessarily associated with gene expression in lung tissues) to visualize their gene expression: CCL18 [18] , CXCL12 [19] , CXCL13 [20] , collagens (COL1A1, COL1A2, COL3A1, COL5A2, COL14A1) [21] , DSP [22] , FAS [23] , IL-8 [24] , MMP1 [25] , MMP2 [26] , MMP7 [25] , MUC5B [22] , SPP1 [27] , PTGS2 [28] , TGFB1 [29] and THY1 [30] . Then, we selected eight IPF experiments performed with lung tissue biopsy samples (GSE32537, GSE21369, GSE24206, GSE94060, GSE72073, GSE35145, GSE31934), and using the PulmonDB website, we created a heatmap with the gene expression patterns and observed that the hierarchical clustering of these data separates IPF and control data sets ( Figure 3A, green and grey clusters at the bottom).…”

“…The third and the fourth annotation rows are sample states, the third annotation row represents the test state and the fourth annotation row is the reference state . A) IPF genes reported being relevant in the literature (CCL18 [18] , CXCL12 [19] , CXCL13 [20] , COL1A1, COL1A2, COL3A1, COL5A2, COL14A1 [21] , DSP [22] , FAS [23] , IL-8 [24] , MMP1 [25] , MMP2 [26] , MMP7 [25] , MUC5B [22] , SPP1 [27] , PTGS2 [28] , TGFB1 [29] and THY1 [30] ). The IPF experiments selected were GSE32537 (pink), GSE21369 (purple), GSE24206 (blue), GSE94060 (grass-green), GSE72073 (lemon yellow), GSE35145 (green), and GSE31934 (yellow).…”