Macrophage polarization is influenced by lipids, which also exert significant control over macrophage functions. Lipids and their metabolites are players in intricate signaling pathways that modulate macrophages’ responses to pathogens, phagocytosis, ferroptosis, and inflammation. This review focuses on lipid metabolism and macrophage functions and addresses potential molecular targets for the treatment of macrophage-related diseases. While lipogenesis is crucial for lipid accumulation and phagocytosis in M1 macrophages, M2 macrophages likely rely on fatty acid β-oxidation to utilize fatty acids as their primary energy source. Cholesterol metabolism, regulated by factors such as SREBPs, PPARs, and LXRs, is associated with the cholesterol efflux capacity and the formation of foam cells (M2-like macrophages). Foam cells, which are targets for atherosclerosis, are associated with an increase in inflammatory cytokines. Lipolysis and fatty acid uptake markers, such as CD36, also contribute to the production of cytokines. Enhancing the immune system through the inhibition of lipid-metabolism-related factors can potentially serve as a targeted approach against tumor cells. Cyclooxygenase inhibitors, which block the conversion of arachidonic acid into various inflammatory mediators, influence macrophage polarization and have generated attention in cancer research. 

Impact of Lipid Metabolism on Macrophage Polarization: Implications for Inflammation and Tumor Immunity

The importance of biologically active lipid mediators, such as prostanoids, leukotrienes, and specialized pro-resolving mediators, in the regulation of inflammation is well established. While the relevance of cholesterol in the context of atherosclerosis is also widely accepted, the role of cholesterol and its biosynthetic precursors on inflammatory processes is less comprehensively described. In the present mini-review, we summarize the current understanding of the inflammation-regulatory properties of cholesterol and relevant biosynthetic intermediates taking into account the implications of different subcellular distributions. Finally, we discuss the inflammation-regulatory effect of cholesterol homeostasis in the context of SARS-CoV-2 infections.

Cholesterol metabolism in the regulation of inflammatory responses

Redox signaling in impaired cascades of wound healing: promising approach.

Acute kidney injury (AKI) is a clinically serious disorder associated with high mortality rates and an increased risk of progression to end-stage renal disease. As an essential supportive treatment for patients with respiratory failure, mechanical ventilation not only save many critically ill patients, but also affect glomerular filtration function by changing renal hemodynamics, neurohumoral and positive end-expiratory pressure, eventually leading to AKI. AMP-activated protein kinase (AMPK), a crucial energy homeostasis regulator, could enhance macrophage phagocytic ability and inhibit inflammation, but whether it can engulf neutrophil extracellular traps (NETs) and alleviate mechanical ventilation-associated AKI is still unclear. In this study, we found that geniposide significantly ameliorated histopathological damage, reduced serum Cre and BUN levels. Besides, geniposide can also induce AMPK activation and enhance macrophage phagocytic ability toward NETs. Moreover, geniposide can markedly reduce the levels of high mobility group box 1 (HMGB1), and these effects were dependent on AMPK-PI3K/Akt signaling. Altogether, these results indicated that geniposide promoted macrophage efferocytosis by inducing AMPK-PI3K/Akt signaling activation, clearing NETs and ameliorating AKI. 

Geniposide ameliorates acute kidney injury via enhancing the phagocytic ability of macrophages towards neutrophil extracellular traps.

Significance of CCNs in liver regeneration

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.

/pdf/activated-cholesterol-metabolism-is-integral-for-innate-22nnxhzu.pdf

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

Sterol regulatory element-binding proteins (SREBPs) are key transcription factors that control fatty acid and cholesterol metabolism. As the major SREBP isoform in macrophages, SREBP1a is also required for inflammatory and phagocytotic functions. However, it is insufficiently understood how SREBP1a is activated by the innate immune response in macrophages. Here, we show that mouse caspase-11 is a novel inflammatory activator of SREBP1a in macrophages. Upon LPS treatment, caspase-11 was found to promote the processing of site-1 protease (S1P), an enzyme that mediates the cleavage and activation of SREBP1. We also determined that caspase-11 directly associates with S1P and cleaves it at a specific site. Furthermore, deletion of the Casp4 gene, which encodes caspase-11, impaired the activation of S1P and SREBP1 as well as altered the expression of genes regulated by SREBP1 in macrophages. These results demonstrate that the caspase-11/S1P pathway activates SREBP1 in response to LPS, thus regulating subsequent macrophage activation.

/pdf/caspase-11-contributes-to-site-1-protease-cleavage-and-um2j673c.pdf

Caspase-11 contributes to site-1 protease cleavage and SREBP1 activation in the inflammatory response of macrophages

Cyclic stretch regulates immune responses via tank‐binding kinase 1 expression in macrophages

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

Caspase-11 contributes to site-1 protease cleavage and SREBP1 activation in the inflammatory response of macrophages

Cyclic stretch regulates immune responses via tank‐binding kinase 1 expression in macrophages