Human intestinal stromal cells promote homeostasis in normal mucosa but inflammation in Crohn's disease in a retinoic acid-deficient manner

Stromal cell (SC) contributions to intestinal inflammation are inadequately understood. Here we show that CD90+vimentin+SMA- SCs isolated from Crohn's disease intestine (Crohn's SCs) displayed higher levels of spontaneously released and microbiota-induced inflammatory mediators, including IL-6 and TGF-b, and surface adhesion molecules, than SCs isolated from healthy intestine (Normal SCs). Comparative transcriptome analysis confirmed the predominance of upregulated inflammatory response and cytokine signaling genes and pathway molecules in Crohn's SCs. Importantly, intestinal SCs provided retinoic acid (RA), which regulated DC maturation, and in an in vitro cross-talk system E. coli LF82-stimulated Crohn's SCs promoted differentiation of more inflammatory TNFhi/IL-12lo/RAlo DCs and IFN-ghi/IL-17hi effector T cells than Normal SCs. Explaining this finding, Crohn's SCs synthesized less RA and expressed more retinaldehyde reductase DHRS3, which inhibits retinol conversion to retinal, than Normal SCs. Our findings uncover microbe-SC crosstalk in which mucosal SCs initiate and perpetuate DC-driven T-cell-mediated inflammation in Crohn's disease. Overall design: 14 samples were analyzed, half the samples were controls