Triglyceride-Rich Lipoproteins Modulate the Distribution and Extravasation of Ly6C/Gr1low Monocytes

Abstract

SummaryMonocytes are heterogeneous effector cells involved in the maintenance and restoration of tissue integrity. However, their response to hyperlipidemia remains poorly understood. Here, we report that in the presence of elevated levels of triglyceride-rich lipoproteins, induced by administration of poloxamer 407, the blood numbers of non-classical Ly6C/Gr1low monocytes drop, while the number of bone marrow progenitors remains similar. We observed an increased crawling and retention of the Gr1low monocytes at the endothelial interface and a marked accumulation of CD68+ macrophages in several organs. Hypertriglyceridemia was accompanied by an increased expression of tissue, and plasma CCL4 and blood Gr1low monocyte depletion involved a pertussis-toxin-sensitive receptor axis. Collectively, these findings demonstrate that a triglyceride-rich environment can alter blood monocyte distribution, promoting the extravasation of Gr1low cells. The behavior of these cells in response to dyslipidemia highlights the significant impact that high levels of triglyceride-rich lipoproteins may have on innate immune cells.

Development of a novel model of hypertriglyceridemic acute pancreatitis in mice

“…Consistent with the previous outcomes of Professor Saja17, we found that P-407 could elevate the serum ApoCIII levels which affected the metabolism of triglyceride and induced hypertriglyceridemia (Fig. S1A).…”

“…Saja et al 17. also verified that long-term HTG could cause lipid deposition and macrophages infiltration in heart, liver and kidney.…”

“…Physiological toxicity of P-407 is so low that both short-term and long-term use can induce high serum triglyceride levels in mice14. Saja et al 17. found that serum triglyceride level of mice could rise up to 4000 mg/dl after treated with P-407 for 28 days and long-term HTG can cause lipid deposition in heart, liver and kidney with infiltration of macrophages and other pathological changes.…”

Ly6Clo monocytes drive immunosuppression and confer resistance to anti-VEGFR2 cancer therapy

“…Scale bars: 100 μm (B-E). (31,53), it has now become questionable whether CX3CR1 is important for the process of Ly6C lo monocyte recruitment or not (50). There have also been reports suggesting that CX3CR1 deficiency influences the survival of monocytes (54,55).…”

CD11c/CD18 Signals Very Late Antigen-4 Activation To Initiate Foamy Monocyte Recruitment during the Onset of Hypercholesterolemia

“…(4) A second subset denoted as “patrolling” or anti-inflammatory monocytes that express Ly6C low CCR2 low CX 3 CR1 high in mice and CD14 + CD16 + in humans, recruit to inflamed endothelium early in the process of lesion formation, give rise to CD11c + foamy macrophages, and extravasate at the endothelial interface and accumulate in organs. (7, 8) The propensity for the trafficking and emigration of specific monocyte subsets is dictated by their relative expression of chemokine C-C motif receptor 2 (CCR2), C-C motif receptor 5 (CCR5), and chemokine C-X 3 -C motif receptor 1 (CX 3 CR1) that signal integrin activation and guide cell migration to arterial sites of nascent plaque formation. (7, 8) A direct comparison of inflammatory activation in the context of lipid mediated integrin-dependent recruitment on VCAM-1 between mouse and human monocyte subsets is lacking.…”