Repetitive intradermal bleomycin injections evoke T-helper cell 2 cytokine-driven pulmonary fibrosis

Abstract

IL-4 and IL-13 are major T-helper cell (Th) 2 cytokines implicated in the pathogenesis of several lung diseases, including pulmonary fibrosis. In this study, using a novel repetitive intradermal bleomycin model in which mice develop extensive lung fibrosis and a progressive decline in lung function compared with saline-treated control mice, we investigated profibrotic functions of Th2 cytokines. To determine the role of IL-13 signaling in the pathogenesis of bleomycin-induced pulmonary fibrosis, wild-type, IL-13, and IL-4Rα-deficient mice were treated with bleomycin, and lungs were assessed for changes in lung function and pulmonary fibrosis. Histological staining and lung function measurements demonstrated that collagen deposition and lung function decline were attenuated in mice deficient in either IL-13 or IL-4Rα-driven signaling compared with wild-type mice treated with bleomycin. Furthermore, our results demonstrated that IL-13 and IL-4Rα-driven signaling are involved in excessive migration of macrophages and fibroblasts. Notably, our findings demonstrated that IL-13-driven migration involves increased phospho-focal adhesion kinase signaling and F-actin polymerization. Importantly, in vivo findings demonstrated that IL-13 augments matrix metalloproteinase (MMP)-2 and MMP9 activity that has also been shown to increase migration and invasiveness of fibroblasts in the lungs during bleomycin-induced pulmonary fibrosis. Together, our findings demonstrate a pathogenic role for Th2-cytokine signaling that includes excessive migration and protease activity involved in severe fibrotic lung disease.

Non-Canonical Regulation of Type I Collagen through Promoter Binding of SOX2 and Its Contribution to Ameliorating Pulmonary Fibrosis by Butylidenephthalide

“…Our data showed immune modulation not only in the lung tissues through infiltration of multinucleated giant cells ( Figure 5 B, bleomycin with vehicle treatment), but also in the findings of BAL fluid ( Figure 6 ), such as the IL-6 and IL-1β, that were both decreased in BP-treated groups. Other studies show that evoked T-helper cell 2 (Th2) is related to the excessive migration of macrophages and fibroblasts and resulted in Macrophage Inflammatory Proteins 1(MIP1) augmentation [ 32 ], as well as pulmonary fibrosis, further supporting our data [ 33 ]. Furthermore, our study suggests a possible relationship between inflammation and fibrosis, but the cause/result could not be determined in the current study.…”

Fra-2–expressing macrophages promote lung fibrosis

“…In T-5224-treated lungs, Fra-2 mRNA, protein, and the number of Fra-2-positive cells were decreased, while IL-4 appeared unaffected ( Figure 7, D and E, and Supplemental Figure 9, H and I). detrimental in the early phases after bleomycin treatment, these likely promote subsequent fibrotic events (52,53). IL-4 and IL-13 induce Fra-2 expression in macrophages (ref.…”

Aberrant populations of circulating T follicular helper cells and regulatory B cells underlying idiopathic pulmonary fibrosis

“…The current study showed predominance of Tfh2 cells and inferiority of Tfh17 cells in the patients with IPF. IL-4 and IL-13, which Tfh2 cells are known to produce, strongly promote fibrosis [40], implying a possible involvement of Tfh2 cells in the pathogenesis of IPF. The proportion of Tfh2 cells increases and Tfh1 cells decreases in bronchial asthma and allergic rhinitis [22].…”