Preexisting tissue mechanical hypertension at adherens junctions disrupts apoptotic extrusion in epithelia.

Apical extrusion is a tissue-intrinsic process that allows epithelia to eliminate unfit or surplus cells. This is exemplified by the early extrusion of apoptotic cells, which is critical to maintain the epithelial barrier and prevent inflammation. Apoptotic extrusion is an active mechanical process, which involves mechanotransduction between apoptotic cells and their neighbors, as well as local changes in tissue mechanics. Here we report that the preexisting mechanical tension at adherens junctions (AJs) conditions the efficacy of apoptotic extrusion. Specifically, increasing baseline mechanical tension by overexpression of a phosphomimetic Myosin II regulatory light chain (MRLC) compromises apoptotic extrusion. This occurs when tension is increased in either the apoptotic cell or its surrounding epithelium. Further, we find that the proinflammatory cytokine, TNFα, stimulates Myosin II and increases baseline AJ tension to disrupt apical extrusion, causing apoptotic cells to be retained in monolayers. Importantly, reversal of mechanical tension with an inhibitory MRLC mutant or tropomyosin inhibitors is sufficient to restore apoptotic extrusion in TNFα-treated monolayers. Together, these findings demonstrate that baseline levels of tissue tension are important determinants of apoptotic extrusion, which can potentially be coopted by pathogenetic factors to disrupt the homeostatic response of epithelia to apoptosis.

Apical extrusion prevents apoptosis from activating an acute inflammatory program in epithelia.

Apoptosis is traditionally considered to be an immunologically silent form of cell death. Multiple mechanisms exist to ensure that apoptosis does not stimulate the immune system to cause inflammation or autoimmunity. Against this expectation, we now report that epithelia are programmed to provoke, rather than suppress, inflammation in response to apoptosis. We found that an acute inflammatory response led by neutrophils occurs in zebrafish and cell culture when apoptotic epithelial cells cannot be expelled from the monolayer by apical extrusion. This reflects an intrinsic circuit where ATP released from apoptotic cells stimulates epithelial cells in the immediate vicinity to produce interleukin-8 (IL-8). Apical extrusion therefore prevents inappropriate epithelial inflammation by physically eliminating apoptotic cells before they can activate this pro-inflammatory circuit. This carries the implication that epithelia may be predisposed to inflammation, elicited by sporadic or induced apoptosis, if apical extrusion is compromised.