High-Density Lipoprotein (HDL) Counter-Regulates Serum Amyloid A (SAA)-Induced sPLA2-IIE and sPLA2-V Expression in Macrophages

Abstract

Human serum amyloid A (SAA) has been demonstrated as a chemoattractant and proinflammatory mediator of lethal systemic inflammatory diseases. In the circulation, it can be sequestered by a high-density lipoprotein, HDL, which carries cholesterol, triglycerides, phospholipids and apolipoproteins (Apo-AI). The capture of SAA by HDL results in the displacement of Apo-AI, and the consequent inhibition of SAA’s chemoattractant activities. It was previously unknown whether HDL similarly inhibits SAA-induced sPLA2 expression, as well as the resultant HMGB1 release, nitric oxide (NO) production and autophagy activation. Here we provided compelling evidence that human SAA effectively upregulated the expression and secretion of both sPLA2-IIE and sPLA2-V in murine macrophages, which were attenuated by HDL in a dose-dependent fashion. Similarly, HDL dose-dependently suppressed SAA-induced HMGB1 release, NO production, and autophagy activation. In both RAW 264.7 cells and primary macrophages, HDL inhibited SAA-induced secretion of several cytokines (e.g., IL-6) and chemokines (e.g., MCP-1 and RANTES) that were likely dependent on functional TLR4 signaling. Collectively, these findings suggest that HDL counter-regulates SAA-induced upregulation and secretion of sPLA2-IIE/V in addition to other TLR4-dependent cytokines and chemokines in macrophage cultures.

High-Density Lipoprotein (HDL) Inhibits Serum Amyloid A (SAA)-Induced Vascular and Renal Dysfunctions in Apolipoprotein E-Deficient Mice

“…Regulatory effects of HDL supplementation on SAA's pro-inflammatory bioactivity, including mitigation of production of reactive oxygen species, has been reported in isolated murine macrophage cultures [22,41]. However, in vivo studies on the role of HDL/SAA interactions in complex biological environments are lacking.…”

Low high-density lipoprotein level is correlated with the severity of COVID-19 patients

“…Excessive in ammation is one of the important features of COVID-19 patients, especially in severe and died patients [24,25,26,27], usually manifested by a marked increase in in ammatory factors, such as CRP and interleukins [3,28]. HDL-C is believed to have an inhibitory effect on in ammation [29,30,31]. In this study, patients with low HDL-C showed a higher level of CRP, which suggested that HDL-C may inhibit the in ammatory response and thus play a protective role in COVID-19 patients.…”

High-density lipoproteins during sepsis: from bench to bedside

“…One important finding is that HDLs stimulate the transcriptional regulator ATF3, which downregulates inflammatory pathways that may in turn decrease the inflammatory response in case of sepsis [34]. Moreover, Zhu et al have shown in murine macrophages that human serum amyloid A (SAA) dramatically upregulates the expression and secretion of a group of phospholipases (sPLA2-IIE and sPLA2-V), which are late pro-inflammatory mediators family [35]. In this in vitro study using purified HDL, HDL dosedependently attenuated SAA-induced secretion of both sPLA2-IIE and sPLA2-V. Lastly, Suzuki et al demonstrated that HDLs inhibit a subset of LPS-stimulated macrophage genes that regulate the type I interferon response, independently of sterol metabolism, raising the possibility that regulation of macrophage transcriptome by HDLs might link innate immunity to cardioprotection [36].…”