A Hypothesis Concerning a Potential Involvement of Ceramide in Apoptosis and Acantholysis Induced by Pemphigus Autoantibodies

Figure 3

Hypothesized Involvement of Sphingolipid Metabolism in the Keratinocyte Response to Pemphigus Autoantibodies. Our hypothesis is that pemphigus autoantibodies binding to Dsgs results in the activation of sphingomyelinase (SMase) to produce ceramide and phosphorylcholine. In an attempt to survive, keratinocytes activate sphingomyelin synthase (SM synthase). The result is an increase in phosphorylcholine and diacylglycerol levels and a reduction in phosphatidylcholine. Stimuli that overwhelm the ability of the cell to metabolize ceramide, such as cytokines or ultraviolet (UV) light (or senescence), which increase ceramide levels, are proposed to allow manifestation of pathologic skin lesions. Note that UV light increases ceramide in at least two ways: first, by activation of both SMase-mediated [35] and de novo ceramide production [19] and second, by decreasing ceramidase activity/expression [60]. Ceramidases are key in the response of keratinocytes to UV light because (1) they metabolize ceramide and decrease its levels and (2) they generate sphingosine, which can be converted to S1P (which allows cell survival) by the action of sphingosine kinase. Indeed, knocking down sphingosine kinase sensitizes keratinocytes to UV-induced apoptosis [60]. In addition, ceramide and its metabolites can activate cytosolic phospholipase A2 and cyclooxygenase-2, suggesting that eicosanoids might be elevated and potentially contribute to the pemphigus disease process (reviewed in [56]).