Apolipoprotein CI stimulates the response to lipopolysaccharide and reduces mortality in Gram‐negative sepsis

Abstract

Gram-negative sepsis is a major death cause in intensive care units. Accumulating evidence indicates the protective role of plasma lipoproteins such as high-density lipoprotein (HDL) in sepsis. It has recently been shown that septic HDL is almost depleted from apolipoprotein CI (apoCI), suggesting that apoCI may be a protective factor in sepsis. Sequence analysis revealed that apoCI possesses a highly conserved consensus KVKEKLK binding motif for lipopolysaccharide (LPS), an outer-membrane component of gram-negative bacteria. Through avid binding to LPS involving this motif, apoCI improved the presentation of LPS to macrophages in vitro and in mice, thereby stimulating the inflammatory response to LPS. Moreover, apoCI dose-dependently increased the early inflammatory response to Klebsiella pneumoniae-induced pneumonia, reduced the number of circulating bacteria, and protected mice against fatal sepsis. Our data support the hypothesis that apoCI is a physiological protector against infection by enhancing the early inflammatory response to LPS and suggest that timely increase of apoCI levels could be used to efficiently prevent and treat early sepsis.

Granzymes Regulate Proinflammatory Cytokine Responses

“…In cases where Grs potentiate pathways induced by TLR ligands independent of the Gr catalytic activity (48), the focus should lie on clarifying how Grs modulate these pathways via interaction with signaling molecules. A common characteristic in LPS-enhancing proteins such as LPS-binding protein (71,72), Grs (48), the neutrophil granule protein azurocidin (73,74), high mobility group box-1 protein (75,76), protamines (77), and apolipoprotein C1 (78,79) is the presence of cationic patches of arginines and/or lysines that drive the interaction with LPS. Endocytosis may also play a role, because internalization is required for the stimulating effect of azurocidin on LPS-induced cytokine responses (80).…”

HDL in Infectious Diseases and Sepsis

“…Septic HDLs are almost depleted of apoC-I (Barlage et al 2001). ApoC-I contains a consensus LPS-binding motif and is able to enhance the biological response to LPS thus reducing mortality in mice with Gram-negative-induced sepsis (Berbee et al 2006). In fact, apoC-I binds to LPS and prevents its clearance by the liver and spleen, resulting in the stimulation of the LPS-induced pro-inflammatory response and protection against septic death (Berbee et al 2006).…”

“…ApoC-I contains a consensus LPS-binding motif and is able to enhance the biological response to LPS thus reducing mortality in mice with Gram-negative-induced sepsis (Berbee et al 2006). In fact, apoC-I binds to LPS and prevents its clearance by the liver and spleen, resulting in the stimulation of the LPS-induced pro-inflammatory response and protection against septic death (Berbee et al 2006). These findings suggest that when LPS is released into the plasma following bacteria proliferation in the blood, apoC-I binds to LPS and presents it to responsive cells such as macrophages, leading to a rapid and enhanced production of pro-inflammatory cytokines, which are essential for effective eradication of the bacterial infection.…”

Apolipoprotein CI enhances the biological response to LPS via the CD14/TLR4 pathway by LPS-binding elements in both its N- and C-terminal helix

“…In fact, we have demonstrated that replacement of the Lys residues within this motif by Ala residues (i.e., AVAEALA ), which neutralizes positive charges without changing the protein structure, decreased the binding to LPS and partly reduced the ability of apoCI to stimulate the LPS-induced TNF ␣ response ( 19 ). However, in addition to the KVKEKLK motif, apoCI contains a number of alternating cationic/hydrophobic motifs throughout its structure.…”