Crosstalk between plasmacytoid dendritic cells and fibroblasts: the role of pDC in systemic sclerosis

• Autor(a) principal: Silva, Inês Maria Santos
• Data de Publicação: 2022
• Tipo de documento: Dissertação
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10773/35663
• topic: pDC; Fibroblast; Fibrosis; Inflammation; ER stress; Systemic sclerosis

Systemic sclerosis (SSc) is a rheumatic autoimmune disease characterized by progressive fibrosis of the skin that can extend to internal organs and tissues. Patients with SSc often exhibit a progressive phenotype with self-sustaining lung fibrosis for which there are scarce effective therapies. Plasmacytoid Dendritic Cells (pDC) are involved in the progression of the disease, particularly in the development of fibrosis. However, the mechanisms behind the role of pDC in fibrosis are still poorly understood. Endoplasmic reticulum (ER) stress has been implicated in both fibrotic disorders and autoimmune diseases, including SSc. ER stress is also known to affect pDC activation, but the impact of this regulation has not been addressed in fibrotic pathologies. Therefore, we aim to dissect the outcome of pDC interactions with human lung fibroblasts, which might contribute to induce and/or exacerbate fibrosis and understand if ER stress impacts pDC-fibroblasts crosstalk. For that we established a co-culture system to analyse interactions between a pDC cell line, CAL-1 cells, and a human lung fibroblasts cell line, IMR-90 cells. It was found that CAL-1 cells physically interact with IMR-90 cells, and that this intercellular crosstalk promotes IL-6 secretion. Interestingly, the secretome produced upon CAL-1 – IMR-90 co-culture was sufficient to induce further IL- 6 production by IMR-90 cells alone, while not affecting fibroblast viability, migration and production of extracellular matrix (ECM) proteins. Simultaneously, it was found that induction of ER stress promoted IL-6 secretion by IMR-90 cells but did not impact co-culture - induced IL-6 secretion. Incubation of IMR-90 cells with conditioned media from ER stressed cells affected cell viability and also promoted an increase in secretion of IL-6 but not ECM production. Overall, our results suggest that CAL-1 cells directly interact with IMR-90 cells and promote inflammation, and that ER stress can play a role in the disease by increasing fibroblasts death and modulating cytokine secretion. We propose that the interaction between pDC and fibroblasts plays a role in the pathogenesis of fibrosis and thus, more studies on the dynamics of their interaction should be done to clarify the mechanisms by which pDC contribute to systemic sclerosis.