Coordinate Stimulation of Macrophages by Microparticles and TLR Ligands Induces Foam Cell Formation

Abstract

Aberrant activation of macrophages in arterial walls by oxidized lipoproteins can lead to atherosclerosis. Oxidized lipoproteins convert macrophages to foam cells through lipid uptake and TLR signaling. To investigate the relative contributions of lipid uptake and TLR signaling in foam cell formation, we established an in vitro assay utilizing liposomes of defined lipid compositions. We found that TLRs signaling through Trif promoted foam cell formation by inducing both NF-KB signaling and Type I IFN production, whereas TLRs that do not induce IFN, like TLR2, did not enhance foam cell formation. Addition of IFNα to TLR2 activator promoted robust foam cell formation. TLR signaling further required PPARα, as inhibition of PPARα blocked foam cell formation. We then investigated the ability of endogenous microparticles (MP) to contribute to foam cell formation. We found that lipid containing MP promoted foam cell formation, which was enhanced by TLR stimulation or IFNα. These MP also stimulated foam cell formation in a human skin model. However, these MP suppressed TNFα production and T cell activation, showing that foam cell formation can occur by immunosuppressive microparticles. Taken together, the data reveal novel signaling requirements for foam cell formation and suggest that uptake of distinct types of MP in the context of activation of multiple distinct TLR can induce foam cell formation.

Intrinsic repair protects cells from pore-forming toxins by microvesicle shedding

“…Exosomes are 40-120 nm cup-shaped structures derived from the lumen of multivesicular bodies, whereas MVs are variably sized plasma membrane derived vesicles. 51 We have previously demonstrated 24,52,53 that vesicles triggered by SLO best fit the definition of MVs. These MV are also not toxic to cells and do not fuse with the plasma membrane of cells that internalize these MV.…”

“…These MV are also not toxic to cells and do not fuse with the plasma membrane of cells that internalize these MV. 52,53 SDS-PAGE and immunoblotting. Samples were resolved on 10% polyacrylamide gels at 90 V/165 min and transferred in ice bath to nitrocellulose in transfer buffer (15.6 mM Tris and 120 mM glycine) at 90 mA for 85 min.…”

Limiting Cholesterol Biosynthetic Flux Spontaneously Engages Type I IFN Signaling

“…Thus, it has been suggested that the influence of type I IFN signaling on the cholesterol homeostasis would serve to limit the availability of lipid metabolites for intracellular organisms. In contrast, other studies have shown that these same inflammatory signals (e.g., TLR3/4 and type I IFNs) increase lipid uptake from environmental sources, resulting in the accumulation of neutral lipids and ultimately facilitating foam cell formation (Dushkin and Kovshik, 2013; Funk et al, 1993; Huang et al, 2014; Keyel et al, 2012). Thus, it remains unclear if the purpose of type I IFN-mediated metabolic reprogramming is to specifically limit the availability of lipid metabolites (e.g., cholesterol) for pathogens as been proposed, or if there are alternative reasons for the selective reprogramming of flux through the cholesterol biosynthetic pathway.…”

Lipid body accumulation alters calcium signaling dynamics in immune cells

“…In addition to this pathophysiology, there is also well-established plasticity in the numbers of lipid bodies in macrophages and other immunocytes. Here, lipid bodies (LB) hyper-accumulate in response to bacterial and parasitic infection [4, 5] and other inflammatory presentations, such as arthritic joint leukocytes [6], lavage of patients with acute respiratory distress [7], peripheral blood leukocytes in sepsis [8, 9] and sites of mycobacterial infection [10, 11]. There is also evidence that endocrine inputs relevant to metabolic syndrome and obesity can alter lipid storage in immunocytes.…”