Activated cholesterol metabolism is integral for innate macrophage responses by amplifying Myd88 signaling
Sumio Hayakawa, … , Ichiro Manabe, Yumiko Oishi
Sumio Hayakawa, … , Ichiro Manabe, Yumiko Oishi
Published November 22, 2022
Citation Information: JCI Insight. 2022;7(22):e138539. https://doi.org/10.1172/jci.insight.138539.
View: Text | PDF
Research Article Inflammation Vascular biology

Activated cholesterol metabolism is integral for innate macrophage responses by amplifying Myd88 signaling

Abstract

Recent studies have shown that cellular metabolism is tightly linked to the regulation of immune cells. Here, we show that activation of cholesterol metabolism, involving cholesterol uptake, synthesis, and autophagy/lipophagy, is integral to innate immune responses in macrophages. In particular, cholesterol accumulation within endosomes and lysosomes is a hallmark of the cellular cholesterol dynamics elicited by Toll-like receptor 4 activation and is required for amplification of myeloid differentiation primary response 88 (Myd88) signaling. Mechanistically, Myd88 binds cholesterol via its CLR recognition/interaction amino acid consensus domain, which promotes the protein’s self-oligomerization. Moreover, a novel supramolecular compound, polyrotaxane (PRX), inhibited Myd88‑dependent inflammatory macrophage activation by decreasing endolysosomal cholesterol via promotion of cholesterol trafficking and efflux. PRX activated liver X receptor, which led to upregulation of ATP binding cassette transporter A1, thereby promoting cholesterol efflux. PRX also inhibited atherogenesis in Ldlr–/– mice. In humans, cholesterol levels in circulating monocytes correlated positively with the severity of atherosclerosis. These findings demonstrate that dynamic changes in cholesterol metabolism are mechanistically linked to Myd88‑dependent inflammatory programs in macrophages and support the notion that cellular cholesterol metabolism is integral to innate activation of macrophages and is a potential therapeutic and diagnostic target for inflammatory diseases.

Authors

Sumio Hayakawa, Atsushi Tamura, Nikita Nikiforov, Hiroyuki Koike, Fujimi Kudo, Yinglan Cheng, Takuro Miyazaki, Marina Kubekina, Tatiana V. Kirichenko, Alexander N. Orekhov, Nobuhiko Yui, Ichiro Manabe, Yumiko Oishi

×

Figure 9

PRX suppresses atherogenesis in Ldlr–/– mice.

Options: View larger image (or click on image) Download as PowerPoint
PRX suppresses atherogenesis in Ldlr–/– mice. (A) Male Ldlr–/– mice were...
(A) Male Ldlr–/– mice were fed a high-cholesterol diet for 11 weeks, with or without subcutaneous PRX injection (1,000 mg/kg BW every 2 days). Aortic atheromatous lesions were visualized after staining with Oil Red O. Oil Red O–positive areas were quantified and normalized with the entire aortic area. n = 11 in each group. *P < 0.05. Student’s 2-tailed t test. (B) Representative photographs of aortic sinuses from Ldlr–/– mice treated with PBS or PRX. Sections were analyzed by staining with hematoxylin-eosin (H&E), Oil Red O, and Masson’s trichrome. Scale bars, 200 μm or 100 μm (second H&E column). (C) Atherosclerotic lesion, necrotic core, and Oil Red O–positive areas were quantified and normalized to the control values (PBS). n = 10 in each group. **P < 0.01, *P < 0.05. Student’s 2-tailed t test. (D) Flow cytometric analysis of cells from thoracic aortas of mice treated with PRX or PBS. Shown are fractions of CD11b+Ly6G–F4/80+ macrophages among the total live cells. n = 6–7 mice for each group. **P < 0.01, Student’s 2-tailed t test. (E) TNF-α expression in CD11b+Ly6G–F4/80+ macrophages. Note that there were fewer cells expressing higher levels of TNF-α in the PRX-treated group. n = 4 mice for each group. *P < 0.05, Student’s 2-tailed t test. (F) Relative mRNA expression of proinflammatory genes in the aorta. *P < 0.05, **P < 0.01, Student’s 2-tailed t test. Data shown as mean ± SD in all panels where P values are shown.