Figure 7. TNF-α promotes netrin-1 through bystander effects.

A Normal colon crypt: stem cells produce the terminally differentiated epithelial cells within a crypt; netrin-1 is constitutively produced by epithelial cells at crypt base and blocks apoptosis until cells migrate to the top of the crypt; macrophages are quiescent in the absence of a specific bacterial trigger. B In Il10^−/− mice, colonizing E. faecalis translocate intact epithelium (presumably through M cells as overlying mucus poses a barrier to commensal bacterial interaction with epithelial cells) and activates tissue macrophages to produce TNF-α. C Inset of epithelial cell: TNF-α mediates bystander effects by binding Tnfrsf1b receptors on epithelial cells to activate NF-κB and increase netrin-1; netrin-1 acts in an autocrine and/or paracrine fashion to bind dependence receptors (e.g., DCC or UNC5H) and provides anti-apoptotic signals for epithelial cells resulting in elongated crypts.