Abstract
Chronic graft-versus-host disease (cGVHD) is a notorious complication of allogeneic hematopoietic stem cell transplantation and causes disabling systemic inflammation and fibrosis. In this novel study, we focused on a relationship between endoplasmic reticulum (ER) stress and cGVHD, and aimed to create effective treatment of cGVHD. A series of experiments were conducted using a mouse model of cGVHD. Our data suggested (1) that ER stress was elevated in organs affected by cGVHD and (2) that 4-phenylbutyric acid (PBA) could reduce cGVHD-induced ER stress and thereby alleviate systemic inflammation and fibrosis. Because fibroblasts are thought to be implicated in cGVHD-elicited fibrosis and because macrophages are reported to play a role in the development of cGVHD, we investigated cGVHD-triggered ER stress in fibroblasts and macrophages. Our investigation demonstrated (1) that indicators for ER stress and activation markers for fibroblasts were elevated in cGVHD-affected lacrimal gland fibroblasts and (2) that they could be reduced by PBA. Our work also indicated that splenic macrophages from PBA-dosed mice exhibited the lower levels of ER stress and M2 macrophage markers than those from cGVHD-affected mice. Collectively, this study suggests that the reduction of ER stress utilizing PBA can be a clinically translatable method to treat systemic cGVHD.
Highlights
Literature precedent indicates that endoplasmic reticulum (ER) stress plays a contributory role in chronic inflammation and age-related diseases[16,17]
The initial venture toward our overarching aim was to investigate whether ER stress was elevated in Chronic graft-versus-host disease (cGVHD)-affected organs by measuring ER stress markers
Real-time quantitative polymerase chain reaction (PCR) and immunoblot analysis suggested (1) that the ER stress indicators glucose regulated protein 78 (GRP78), C/EBP homologous protein (CHOP), p-PKR-like ER kinase (PERK), p-eIF2α, and p-IRE1αwere increased in murine organs affected by cGVHD compared with control subjects and (2) that the following two inflammatory molecules were activated and/or augmented in the cGVHD-impaired organs: NF-κB and thioredoxin interaction protein (TXNIP) (Fig. 1A–C)
Summary
Literature precedent indicates that endoplasmic reticulum (ER) stress plays a contributory role in chronic inflammation and age-related diseases[16,17]. The unsuccessful UPR leads to the expression of (1) the proinflammatory molecules thioredoxin interaction protein (TXNIP) and transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and (2) the apoptotic protein C/EBP homologous protein (CHOP)[21,22,23,24,25,26]. Based on the previous findings, we envisaged (1) that ER stress would be increased in cGVHD-impaired organs and (2) that mitigation of ER stress could be effective treatment of cGVHD. To achieve this goal, we used 4-phenylbutyric acid (PBA) as an ER stress reducer. We report the world-first strategy to treat cGVHD using the ER stress reducer PBA
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