Epithelial cells release adenosine to promote local TNF production in response to polarity disruption.

Disruption of epithelial integrity contributes to chronic inflammatory disorders through persistent activation of stress signalling. Here we uncover a mechanism whereby disruption of apico-basal polarity promotes stress signalling. We show that depletion of Scribbled (Scrib), a baso-lateral determinant, causes epithelial cells to release adenosine through equilibrative channels into the extracellular space. Autocrine activation of the adenosine receptor leads to transcriptional upregulation of TNF, which in turn boosts the activity of JNK signalling. Thus, disruption of cell polarity feeds into a well-established stress pathway through the intermediary of an adenosine signalling branch. Although this regulatory input could help ensuring an effective response to acute polarity stress, we suggest that it becomes deleterious in situations of low-grade chronic disruption by provoking a private inflammatory-like TNF-driven response within the polarity-deficient epithelium.