首页|Bactericidal ability of target acidic phospholipids and phagocy-tosis of CDC42 GTPase-mediated cytoskeletal rearrangement underlie functional conservation of CXCL12 in vertebrates
Bactericidal ability of target acidic phospholipids and phagocy-tosis of CDC42 GTPase-mediated cytoskeletal rearrangement underlie functional conservation of CXCL12 in vertebrates
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Chemokine CXCL12 plays a crucial role in both direct bactericidal activity and phagocytosis in humans.However,the mechanisms and evolutionary functions of these processes in vertebrates remain largely unknown.In this study,we found that the direct bactericidal activity of CXCL12 is highly conserved across various vertebrate lineages,including Arctic lamprey(Lampetra japonica),Basking shark(Cetorhinus maximus),grass carp(Ctenopharyngodon idella),Western clawed frog(Xenopus tropicalis),Green anole(Anolis carolinensis),chicken(Gallus gallus),and human(Homo sapiens).CXCL12 also has been shown to promote phagocytosis in lower and higher vertebrates.We then employed C.idella CXCL12a(CiCXCL12a)as a model to further investigate its immune functions and underlying mechanisms.CiCXCL12a exerts direct broad-spectrum antibacterial activity by targeting bacterial acidic phospholipids,resulting in bacterial cell membrane per-foration,and eventual lysis.Monocytes/macrophages are attracted to the infection sites for phagocytosis through the rapid production of CiCXCL12a during bacterial infection.CiCXCL12a induces CDC42 and CDC42 GTPase activation,which in turn mediates F-actin poly-merization and cytoskeletal rearrangement.The interaction between F-actin and Aeromonas hydrophila facilitates bacterial internalization into monocytes/macrophages.Additionally,A.hydrophila is colocalized within early endosomes,late endosomes and lysosomes,ultimately degrading within phagolysosomes.CiCXCL12a also activates PI3K-AKT,JAK-STAT5 and MAPK-ERK signaling pathways.Notably,only the PI3K-AKT signaling pathway inhibits LPS-induced monocyte/macrophage apoptosis.Thus,CiCXCL12a plays key roles in reducing tissue bacterial loads,attenuating organ injury,and decreasing mortality rates.Altogether,our findings elucidate the conserved mechanisms underlying CXCL12-mediated bactericidal activity and phagocytosis,providing novel perspectives into the immune functions of CXCL12 in vertebrates.
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