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

Intestinal stromal cells (SCs), which synthesize the extracellular matrix that gives the mucosa its structure, are newly appreciated to play a role in mucosal inflammation. Here, we show that human intestinal vimentin⁺CD90⁺smooth muscle actin⁻ SCs synthesize retinoic acid (RA) at levels equivalent to intestinal epithelial cells, a function in the human intestine previously attributed exclusively to epithelial cells. Crohn’s disease SCs (Crohn’s SCs), however, synthesized markedly less RA than SCs from healthy intestine (normal SCs). We also show that microbe-stimulated Crohn’s SCs, which are more inflammatory than stimulated normal SCs, induced less RA-regulated differentiation of mucosal dendritic cells (DCs) (circulating pre-DCs and monocyte-derived DCs), leading to the generation of more potent inflammatory interferon-γ^hi/interleukin-17^hi T cells than normal SCs. Explaining these results, Crohn’s SCs expressed more DHRS3, a retinaldehyde reductase that inhibits retinol conversion to retinal and, thus, synthesized less RA than normal SCs. These findings uncover a microbe–SC–DC crosstalk in which luminal microbes induce Crohn’s disease SCs to initiate and perpetuate inflammation through impaired synthesis of RA.