HDL and apoA-I as Members of the Innate Immune System

The innate immune system represents the first line of defense against infectious agents and modified self-antigens (modified/oxidized lipids and apoptotic cells) consisting of a cellular and a humoral part. Cellular components are represented mostly by antigen-presenting cells (APCs), such as macrophages and dendritic cells, whereas the humoral counterpart is mostly represented by the pentraxin family and the complement system. Being extensively conserved throughout the evolution, and existing in early evolutionary species not affected by CVD (Babin et al. 1997), HDLs are believed to be part of the humoral innate immune system, helping mammals to fight against invading pathogens. Indeed, thanks to the presence of different proteins on HDL molecules, such as apoA-I, apoL-1, and haptoglobin-related proteins, HDLs are known to behave as antimicrobial agents protecting mammals against different parasites and bacteria, such as Trypanosoma brucei, Escherichia coli, and Klebsiella pneumoniae (Shiflett et al. 2005; Beck et al. 2013) (see chapter “HDL in Infectious Diseases and Sepsis”).

Furthermore, on top of interfering directly with invading pathogens, HDL and apoA-I also modulate the APR-induced activation of the innate immune system by both neutralizing major bacterial membrane components, such as LPS of Gramnegative bacteria and LTA of Gram-positive bacteria, and modulating the proinflammatory signaling at the level of innate receptors, such as Toll-like receptors (TLRs), scavenger receptors (SRs), and Nod-like receptors (NLRs). Mathison and colleagues demonstrated for the first time in 1979 that HDL could reduce LPS toxicity in vivo (Mathison and Ulevitch 1979). This observation was subsequently inferred to the ability of HDL to sequester LPS, preventing the latter to elicit a proinflammatory response through TLR4/CD14 complex interaction (Levine et al. 1993). Later on, this scavenging effect of HDL was attributed to a specific apoA-I region on the N-terminal segment of apoA-I (aa: 52–74) (Wang et al. 2008). More recently, apoA-I was shown to have a similar ability to bind to LTA and to neutralize its proinflammatory effect (Jiao and Wu 2008). Interestingly, this effect was much weaker with HDL, suggesting that apoA-I is the key effector of LTA scavenging (Grunfeld et al. 1999). The integrity of innate immune receptor signaling is largely dependent on their localization into lipid rafts, as well as on the integrity of the latter (Triantafilou et al. 2002). In this respect, apoA-I has been shown to deplete cholesterol from lipid rafts, leading to a decrease in TLR4 functionality, followed by an inhibition of LPS-induced inflammatory responses (Triantafilou et al. 2002). In the same line of thought, on top of altering the lipid raft composition, apoA-I has also been shown to impede TLR4 transport into lipid rafts, thereby preventing its ability to promote an efficient proinflammatory response (Smythies et al. 2010; Cheng et al. 2012). These findings indicate that apoA-I and HDL, albeit to a lesser extent, can effectively modulate TLR activity at the preceptor, receptor, and post-receptor levels (De Nardo et al. 2014).

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