Functional consequences of sphingomyelinase-induced changes in erythrocyte membrane structure

Abstract

Inflammation enhances the secretion of sphingomyelinases (SMases). SMases catalyze the hydrolysis of sphingomyelin into phosphocholine and ceramide. In erythrocytes, ceramide formation leads to exposure of the removal signal phosphatidylserine (PS), creating a potential link between SMase activity and anemia of inflammation. Therefore, we studied the effects of SMase on various pathophysiologically relevant parameters of erythrocyte homeostasis. Time-lapse confocal microscopy revealed a SMase-induced transition from the discoid to a spherical shape, followed by PS exposure, and finally loss of cytoplasmic content. Also, SMase treatment resulted in ceramide-associated alterations in membrane–cytoskeleton interactions and membrane organization, including microdomain formation. Furthermore, we observed increases in membrane fragility, vesiculation and invagination, and large protein clusters. These changes were associated with enhanced erythrocyte retention in a spleen-mimicking model. Erythrocyte storage under blood bank conditions and during physiological aging increased the sensitivity to SMase. A low SMase activity already induced morphological and structural changes, demonstrating the potential of SMase to disturb erythrocyte homeostasis. Our analyses provide a comprehensive picture in which ceramide-induced changes in membrane microdomain organization disrupt the membrane–cytoskeleton interaction and membrane integrity, leading to vesiculation, reduced deformability, and finally loss of erythrocyte content. Understanding these processes is highly relevant for understanding anemia during chronic inflammation, especially in critically ill patients receiving blood transfusions.

Increased localization of APP‐C99 in mitochondria‐associated ER membranes causes mitochondrial dysfunction in Alzheimer disease

“…First, as MAM contains γ‐secretase and SMase activities, our data help explain why changes in APP processing can induce alterations in sphingolipid regulation (Filippov et al , 2012; Lee et al , 2014). Second, upregulation of SMase and the resulting increase in ceramide are known to alter the size and composition of lipid raft domains (Dinkla et al , 2012), such as MAM. Therefore, an increased localization of C99 in MAM in AD may explain the upregulation of ER–mitochondria connections and MAM functionality seen in the disease (Area‐Gomez et al , 2012; Hedskog et al , 2013).…”

Secretory sphingomyelinase in health and disease

“…In erythrocytes, the activity of sphingomyelinase induces a transition from a discoid to spherical shape, followed by phosphatidylserine exposure and finally a loss of cytoplasmic content (Dinkla et al, 2012). In the context of elevated S-ASM levels in sepsis (Claus et al, 2005;Kott et al, 2014), the resulting enhanced erythrocyte clearance is likely to contribute to anemia.…”

“…In the context of elevated S-ASM levels in sepsis (Claus et al, 2005;Kott et al, 2014), the resulting enhanced erythrocyte clearance is likely to contribute to anemia. The sensitivity of erythrocytes increases further during blood bank storage and physiological aging (Dinkla et al, 2012).…”

Acid sphingomyelinase is activated in sickle cell erythrocytes and contributes to inflammatory microparticle generation in SCD

“…[4][5][6][7][8] Furthermore, SMase has been implicated in lipid microdomain formation, membrane fragility, vesiculation, and MP formation. 9,10 Although the orientation of membrane lipids in SCD and other hemolytic anemias has been studied, the consequences of altered distribution and metabolism of sphingolipids have been largely unexplored.…”

“…Acid SMase is secreted from endothelial and myeloid cells, 11 and erythrocyte clearance and chronic inflammation, both of which occur in SCD and enhance the secretion of acid SMase. 9,[12][13][14] The role of acid SMase, and sphingolipid dysregulation more generally, has not been studied in the context of SCD.…”