Macrophage galactose lectin is critical for Kupffer cells to clear aged platelets

Abstract

Every day, megakaryocytes produce billions of platelets that circulate for several days and eventually are cleared by the liver. The exact removal mechanism, however, remains unclear. Loss of sialic acid residues is thought to feature in the aging and clearance of platelets. Using state-of-the-art spinning disk intravital microscopy to delineate the different compartments and cells of the mouse liver, we observed rapid accumulation of desialylated platelets predominantly on Kupffer cells, with only a few on endothelial cells and none on hepatocytes. Kupffer cell depletion prevented the removal of aged platelets from circulation. Ashwell-Morell receptor (AMR) deficiency alone had little effect on platelet uptake. Macrophage galactose lectin (MGL) together with AMR mediated clearance of desialylated or cold-stored platelets by Kupffer cells. Effective clearance is critical, as mice with an aged platelet population displayed a bleeding phenotype. Our data provide evidence that the MGL of Kupffer cells plays a significant role in the removal of desialylated platelets through a collaboration with the AMR, thereby maintaining a healthy and functional platelet compartment.

Hepatic macrophages in liver homeostasis and diseases-diversity, plasticity and therapeutic opportunities

“…17 Functionality of hepatic macrophages during homeostasis KCs play a critical role in maintaining homeostasis of the liver and the whole body through five major functions. These include (i) clearance of cellular debris and metabolic waste, [18][19][20] (ii) maintenance of iron homeostasis via phagocytosis of red blood cells (RBCs) and the subsequent recycling of iron, [21][22][23][24] (iii) regulation of cholesterol homeostasis through the production of cholesteryl ester transfer protein, which is important for decreasing circulating high-density lipoprotein-cholesterol levels and increasing very low-density lipoprotein-cholesterol levels, 25 (iv) mediation of antimicrobial defense, 26,27 and (v) promotion of immunological tolerance. 28,29 Clearance of damaged or aged RBCs is crucial for systemic homeostasis.…”

“…Indeed, KC depletion by liposome-entrapped clodronate (CLDN) causes the accumulation of aged platelets in the blood, leading to impaired coagulation. 18 The expression of macrophage galactose lectin is important for KC-mediated platelet clearance. 18 KCs reside along sinusoids and serve as the first-line defense against pathogens by efficiently recognizing and removing bloodborne Gram-positive bacteria.…”

“…18 The expression of macrophage galactose lectin is important for KC-mediated platelet clearance. 18 KCs reside along sinusoids and serve as the first-line defense against pathogens by efficiently recognizing and removing bloodborne Gram-positive bacteria. Complement receptor of immunoglobulin superfamily (CRIg), which is uniquely expressed on KCs in the liver, rapidly recognizes and binds to lipoteichoic acid (LTA), particularly on Gram-positive bacteria.…”

Regulation of Platelet Production and Life Span: Role of Bcl-xL and Potential Implications for Human Platelet Diseases

“…If, therefore, platelet in vivo apoptosis is not simply the result of Bcl-xL degradation over time, two hypotheses remain on what triggers platelet apoptosis in vivo ( Figure 2 ): (1) a direct activation of Bak by an unknown factor or (2) the function of Bcl-xL is modified in aged platelets that may induce a decreased inhibitory activity on Bak. Furthermore, studies have shown that cell surface glycoproteins are modified in aged platelets leading to their recognition and clearance by liver macrophages and hepatocytes [ 50 , 51 ]. Future studies are needed to determine if there is a link between platelet age-dependent changes in glycosylation and platelet apoptosis or if these processes are distinct.…”

Live Imaging of Innate and Adaptive Immune Responses in the Liver

“…Recent imaging-based studies demonstrated that aged or injured platelets were trapped and removed by KC but neither hepatocytes nor LSECs. This function of KCs relied on a collaboration of their macrophage galactose lectin and Ashwell-Morell receptor to capture desialylated platelets from the blood (36). Whereas C-type lectin domain family 4 member f (CLEC4f) as the KC specific receptor was proposed to capture desialylated platelets in mouse (37), this receptor was absent in human (38).…”