Programmed cell death of keratinocytes culminates in apoptotic secretion of a humectant upon secretagogue action of acetylcholine

The programmed cell death of the stratified squamous epithelial cells compr ising human epidermis culminates in abrupt transition of viable granular ke ratinocytes (KC) into dead corneocytes sloughed by the skin. The granular c ell-corneocyte transition is associated with a loss in volume and dry cell weight but the mechanism for and biological significance of this form of ke ratinocyte apoptosis remain obscure. We show that terminally differentiated KC extrude into the intercellular spaces of living epidermis the cytoplasm ic buds containing randomly congregated components of the cytosol as well a s filaggrin, a precursor of the natural moisturizing factor. The discharge of secretory product is reminiscent of holocrine secretion, suggesting the term 'apoptotic secretion' for this novel, essential step in the process of cornification. The secretory product may become a part of the glycocalyx ( a.k.a. 'intercellular cement substance' of epidermis) and serve as a humect ant that counterbalances the osmotic pressure imposed by the natural moistu rizing factor located in the stratum corneum comprised by corneocytes, The apoptotic secretion commences upon secretagouge action of acetylcholine whi ch is synthesized and released by KC, A combination of a cholinergic nicoti nic agonist and a muscarinic antagonist which increases intracellular calci um levels is required to trigger the apoptotic secretion. Analysis of the r elative amounts of cholinergic enzymes and receptors expressed by KC capabl e of secretion and the pharmacological profiles of secretion regulation rev ealed an upward concentration gradient of free acetylcholine in epidermis w hich may provide for its unopposed secretagogue action via the mi muscarini c and the alpha7, and alpha9 nicotinic receptor types expressed by KC at th e latest stage of their development in the epidermis.