Role of immunoproteasomes in fibrotic remodeling

Abstract

Immunoproteasomes (IP) are the main type of protein degrading proteasomes in immune cells. They can be induced in non-parenchymal cells upon inflammatory activation. Our recent analysis identified markedly induced expression of IPs in parenchymal cells in idiopathic pulmonary fibrosis (IPF). We here investigate the role of IP in fibrotic remodeling and fibroblast activation. IP expression was elevated in bleomycin-induced lung fibrosis and oxalate-induced kidney fibrosis in mice as demonstrated by Western blotting of fibrotic tissue. Interestingly, the profibrotic cytokine TGFs decreased the amount of immunoproteasomes in primary human lung fibroblasts (phLF), both on RNA and protein level and also reduced IP activity in myodifferentiated phLF. Specific inhibition of the immunoproteasome, however, did not alter fibrotic marker gene expression in vitro. Similarly, deficiency of the single immunosubunit LMP2 did not significantly influence TGFs–induced myofibroblast differentiation in primary murine lung fibroblasts (pmLF) compared to wildtype littermates. In a next step, we will perform bleomycin challenge on LMP2-/- and LMP7-/- mice as a causal approach to investigate the role of immunoproteasomes in fibrotic lung remodeling. In conclusion, immunoproteasomes are activated upon fibrotic tissue remodeling but downregulated by TGFs in isolated lung fibroblasts suggesting that other stimuli promote immunoproteasome activation in fibrosis. The use of specific immunoproteasome inhibitors in the model of bleomycin-induced lung fibrosis will help to identify the role of immunoproteasomes in pulmonary fibrosis and may identify immunoproteasomes as a potential therapeutic target in chronic lung disease.