102 Article Swipe
YOU?
·
· 2024
· Open Access
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· DOI: https://doi.org/10.4049/jimmunol.212.supp.0763.5382
· OA: W4404167405
Inflammation-associated fibroblasts (IAFs) are a cell population that emerges in tissue inflammation. In inflammatory bowel diseases (IBD), IAFs correlate with disease severity and are enriched in colon tissue of patients refractory to anti-TNF therapy. IAFs can amplify tissue inflammation and mediate pro-fibrotic matrix remodeling and therefore represent a novel cellular target for treating inflammatory diseases like IBD. To explore the cellular and molecular pathways that mediate transition to an IAF-like phenotype, we developed a co-culture of human PBMCs and primary colonic fibroblasts to study stromal-immune crosstalk in promoting IAFs. Culturing primed PBMCs with fibroblasts in direct contact drives fibroblast transition to an IAF phenotype through upregulation of inflammatory mediators, evidenced by modulation of gene expression and secreted protein profiles. Single-cell RNAseq revealed IAF development is influenced by PBMC priming conditions. Exposure to LPS-primed PBMCs promoted a matrix-remodeling IAF phenotype while PHA-primed PBMCs promoted an immunomodulatory IAF. IAF activation can be dampened by inhibitors, including TNF and JAK inhibitors. This co-culture system can therefore be used to define mechanisms mediating IAF transition and identify IAF states that can be tailored to accentuate pathways for focused interrogation. We aim to leverage this system to identify novel targets and test prospective therapies to modulate IAF transition and downstream activity.
