Mechanism for phosphatidylserine-dependent erythrophagocytosis in mouse liver

Abstract

IntroductionThe rapid removal of damaged and aged RBCs from the peripheral circulation is important for tissue homeostasis. Based on a life span of 120 days, 170 billion RBCs must be removed daily from the blood circulation by the liver and spleen. Phagocytes need to engulf 2 million RBCs per second. 1 Clearance of aged and damaged RBCs is mediated by the recognition of phosphatidylserine (PS) on the cell surface. 2,3 Kupffer cells in the liver are known to be responsible for engulfing damaged RBCs in a PS-dependent manner. 4 The number of PS-exposed RBCs to be removed is remarkably increased in patients with several hemolytic anemia, including sickle cell disease, ␤-thalassemia, malaria, and chronic renal failure. [5][6][7][8] Furthermore, apoptotic and senescent neutrophils are almost entirely eliminated from the circulation (clearance halftime ϭ 6.7 hours) by Kupffer cells in the liver, but rarely by macrophages in the spleen, lung, and peripheral blood. 9,10 Kupffer cells are also involved in the clearance of macromolecules and pathogens. 11 The many functions of Kupffer cells suggest that an auxiliary mechanism is required for apoptotic and senescent cell clearance in the liver.Stabilin-1 and stabilin-2 are type I transmembrane receptors with multiple functions, including cell adhesion, endocytosis, and phagocytosis. They are expressed in certain populations of macrophages as well as in sinusoidal endothelial cells in the liver, spleen, and lymph nodes. [12][13][14][15] Although stabilin-1 and stabilin-2 have different ligands during endocytosis, 16 they share common functions such as cell-cell adhesion. 17,18 Recently, stabilin-2 was suggested as a novel member of PS-receptor along with Tim-4 and BAI1. 15,19,20 More recently, we showed that stabilin-1 is also involved in apoptotic cell clearance via recognition of PS in alternatively activated macrophages. 21 Although stabilin-2 and its functional homolog stabilin-1 are involved in aged and apoptotic cell clearance in macrophages via PS recognition, 15,21 their role as PS receptors in sinusoidal endothelial cells remains an open question. Hepatic sinusoidal endothelial cells (HSECs) are the major cell population of the hepatic sinusoid and play several important roles in the physiology and pathology of the liver, including Ag presentation and clearance of macromolecules and apoptotic cells. 22,23 Thus, we hypothesized that there is a potential mechanism for the efficient removal of aged or damaged RBCs in the liver, where sinusoidal endothelial cells play a role in facilitating clearance by Kupffer cells. In this study, we present evidence that stabilin-1 and stabilin-2 in HSECs function as receptors in the PS-specific sequestration of damaged RBCs for their effective removal from the blood circulation. Methods Mice, reagents, and AbsSix-to 7-week-old male BALB/c mice were used. These mice were maintained under specific pathogen-free conditions, and the use committee established at the Medical College of Kyungpook National University and Kyungpook National...

(+)-SJ733, a clinical candidate for malaria that acts through ATP4 to induce rapid host-mediated clearance of Plasmodium

“…The most obvious explanation for enhanced clearance in vivo is that (+)-SJ733 induces an erythrocyte phenotype leading to rapid clearance such as eryptosis (suicidal erythrocyte death) or senescence, which can be caused by a wide range of stresses (15,16). Eryptotic and senescent erythrocytes share several key features: an increase in exposed phosphatidylserine (PS), increased membrane rigidity, more spherical shape, and decreased size (17,18).…”

A role for activated endothelial cells in red blood cell clearance: implications for vasopathology

“…Notably, hepatic sinusoidal endothelial cells were recently shown to play a role in the sequestration of PS-exposing damaged RBC in the liver. 43 In particular the phagocytic capacity of Küpffer cells in the liver was found to be significantly enhanced by hepatic sinusoidal endothelial cells, mediated by stabilin-1 and stabilin-2. We show here that endothelial cells themselves also exert phagocytic properties, in both static and flow conditions.…”

Physiologically aged red blood cells undergo erythrophagocytosis in vivo but not in vitro

“…52 In the liver, uptake of damaged RBC by liver macrophages (Kupffer cells) is strongly supported by the adjacent sinusoidal cells. 22 Sinusoidal cells scavenge RBC through Stabilin1 and 2, retaining RBC in the vicinity of the macrophages and thus facilitating their phagocytosis. This is an example on how macrophages depend on their tissue environment for efficient EPC.…”

“…9 External exposure of PS was mostly induced by calcium and calciumionophore administration, 15,20 but was also detected after the addition of ribavirin, oxidizing agents, low levels of lead or prolonged incubation in phosphate-buffered saline (PBS). 21,22 The naturally occurring accumulation of antiband 3 antibodies on RBC membranes during aging was mimicked successfully by opsonization of RBC, which led to massive EPC. [23][24][25][26] Chemical oxidation by addition of hydrogen peroxide, tert-butyl hydroperoxide or copper with ascorbate was also used to damage RBC and these damaged RBC were used to mimic sRBC in EPC assays.…”