Endoplasmic reticulum stress and inhibition of apoptotic caspases regulate the life-span of short-lived plasma cells

Abstract

Plasma cells are the terminally differentiated effector cells of the humoral immune system. The majority of plasma cells are short-lived and undergo programmed cell death in the form of apoptosis after few days of intensive immunoglobulin secretion. Despite potentially wide-ranging implications for infection control, auto-immunity, and plasma cell dyscrasias, the mechanisms that govern the initiation and execution of plasma cell apoptosis are poorly understood. In this study, it was found that a sharp increase in endoplasmic reticulum (ER) stress and a substantially decreased tolerance to survive ER stress occur in plasma cells that have completed differentiation and begin to undergo apoptosis. Caspase-12, which has been linked specifically to ER stressinduced apoptosis, is activated during programmed plasma cell death and mediates apoptotic DNA fragmentation and chromatin condensation. In contrast, the major apoptotic effector caspases downstream of the mitochondria become resistant to activation during terminal plasma cell differentiation and are not activated during plasma cell apoptosis. Caspase-3, which acts as the major executioner of apoptosis in most cells, becomes stabilized in its inactive form in plasma cells and human myeloma cell lines. Immunohistochemistry of human lymphoid tissue sections demonstrated that primary plasma cells and myeloma cells undergo spontaneous apoptosis in vivo without activation of caspase-3. Using mouse embryonic fibroblasts double-deficient in caspase-3 and caspase-7, it was found that lack of active executioner caspases substantially delays but does not prevent ER stress-induced apoptosis. These observations suggest that developmentally regulated inhibition of key apoptotic caspases has evolved in plasma cells as a means to delay apoptosis under conditions of ER stress that is linked to immunoglobulin secretion. Overwhelming ER stress ultimately limits the life-span of short-lived plasma cells by inducing apoptosis using alternative mechanism involving caspase-12, which mediates nuclear apoptotic events.