High-density lipoprotein (HDL) and infections: a versatile culprit

For several years, HDL has been referred to as ‘good cholesterol’, exerting a plethora of beneficial effects mainly on cells of the vascular tree. HDL prevents endothelial dysfunction, reduces proinflammatory cell activation, and promotes reverse cholesterol transport. However, many studies questioned this principle of HDL’s protective functions and could intriguingly document that a variety of diseases render HDL dysfunctional. In patients with coronary artery disease, diabetes, or autoimmunological diseases, HDL loses its vasoprotective properties and, in chronic kidney disease, even turns into noxious lipoprotein inducing endothelial dysfunction and increasing arterial blood pressure. Therefore, it is not surprising that neither increased HDL-cholesterol (HDL-C) levels nor single nucleotide polymorphisms (SNPs) associated with elevated HDL-C levels were linked to improved outcomes in patients with prevalent cardiovascular diseases, which is in marked contrast to studies of the general population. In line with these epidemiological findings, studies of HDL-raising therapies by inhibition of the cholesterol ester transfer protein (CETP) yielded neutral (for torcetrapib, dalcetrapib, and evacetrapib) or weakly positive (for anacetrapib) effects. Based on the presence of dysfunctional HDL, particularly in patients with coronary artery disease or myocardial infarction, it makes sense that increasing such ‘dysfunctional HDL’ might not be related to improved outcomes in those patients. Therefore, HDL remains an enigmatic lipoprotein, which cannot be adequately therapeutically targeted. Besides increasing HDL-C, preventing changes of the composition of HDL (such as changes of the proteome or post-translational protein modifications), which are directly linked to the functionality of HDL, has at least the potential to put HDL back in the focus as a therapeutically targetable lipoprotein. However, these drawbacks and recent advances in LDLlowering therapies have pushed HDL somewhat out of the spotlight of cardiovascular medicine. In the current issue of the journal, Madsen and colleagues have opened up a new field of interest in HDL. In two well-characterized and large-scale cohorts of the general population, the authors assessed the association between HDL-C levels and infection-related hospitalization. According to experimental studies demonstrating antiinflammatory effects of HDL, low HDL-C was associated with increased infection risk. Surprisingly, very high HDL-C levels (>93 mg/ dL) were also related to an increased risk for infectious disease events, resulting in a U-shaped association between HDL-C and (bacterial) infections. To strengthen their findings, the authors were able to demonstrate that SNPs in genes encoding hepatic lipoprotein lipase, LIPC, and cholesterol ester transfer protein, CETP, both HDL-C-increasing alleles, were consistently associated with a reduced risk for infections. Because of the low number of viral infection events, the study did primarily identify an association between HDL-C and bacterial infections. It is not unreasonable to explain the association between low HDL-C and increased number of infectious events. HDL may directly reduce the pathogenicity of Gram-positive and Gram-negative bacteria. For 20 years, it has been known that HDL serves as a ‘sponge’, binding bacterial lipopolysaccharide (LPS) from Gramnegative and lipoteichoic acid (LTA) from Gram-positive bacteria. Thereby, HDL has the potential to promote their clearance from the circulation and to prevent an excess of endotoxin. In addition, HDL may also exert an immunomodulatory function by limiting pathogen-mediated activation of the innate immune system. HDL increases the expression of the transcription factor ATF3 in macrophages, which attenuates the production of proinflammatory cytokines after challenge of Toll-like receptors (TLRs) with their ligands such as LPS. Moreover, in endothelial cells, HDL stimulates endothelial nitric oxide (NO) production, which prevents the expression of cell adhesion molecules and, thereby, the interaction between monocytes and endothelial cells, a crucial step in the pathogenesis of an inflammatory response. Furthermore, sphingosine-1 phosphate (S1P), a component of HDL, modulates adaptive immunity by, for instance, increasing the population of regulatory T lymphocytes.