Aug 2026· Cell Proliferation· 0 citations· 64 references
Medicine
TL;DR
Macrophage lipid homeostasis is supported as an important regulator of IVDD‐associated immune dysfunction through senescence‐associated impairment of efferocytosis through senescence‐associated impairment of efferocytosis.
Abstract
ABSTRACT Intervertebral disc degeneration (IVDD) is a major contributor to low back pain, but the immune‐metabolic events that sustain disc inflammation remain poorly defined. Here, we investigated whether disturbed macrophage lipid handling promotes IVDD by coupling cellular senescence to defective efferocytosis. Clinical magnetic resonance imaging and biochemical profiling showed that advanced IVDD was accompanied by increased disc fat fraction and systemic lipid abnormalities. Mendelian randomisation, bulk transcriptomics, machine‐learning modelling and single‐cell RNA sequencing further linked lipid metabolic disturbance to immune remodelling in degenerative discs, and identified TIAM2, SLC44A4, PPT1 and PTGDS as lipid metabolism‐related hub genes associated with IVDD. At the single‐cell level, disc macrophages with low glycerophospholipid metabolism scores showed higher senescence activity, a more inflammatory polarisation state and reduced efferocytosis‐related signatures. Functional studies in bone marrow‐derived macrophages indicated that lipid overload promoted lipid droplet accumulation, lipid peroxidation, impaired lipophagy and cholesterol efflux, activation of the p53/p21 senescence pathway, and reduced apoptotic nucleus pulposus cell clearance. Restoring lipid homeostasis with rosuvastatin enhanced lipophagy, recovered ABCA1/ABCG1‐mediated cholesterol export, attenuated macrophage senescence and inflammatory activation and improved efferocytosis. In a rat needle puncture model, local rosuvastatin delivery alleviated disc structural damage, preserved proteoglycan content, balanced extracellular matrix metabolism and reduced macrophage senescence and inflammatory markers. In conclusion, this study supports macrophage lipid homeostasis as an important regulator of IVDD‐associated immune dysfunction through senescence‐associated impairment of efferocytosis.
ABSTRACT Intervertebral disc degeneration (IVDD) constitutes a leading contributor to the development of low back pain, yet its epigenetic regulation remains unclear. Here, we identify a mechanism by which N6‐methyladenosine (m6A) RNA modification contributes to lysosomal membrane permeabilization (LMP) in IVDD. Single‐cell transcriptomic analysis of human nucleus pulposus (NP) tissues shows an enrichment of lysosomal pathway genes in severely degenerated NP cells, along with LMP and disrupted mitophagy flux. We further show that interleukin‐1β (IL‐1β) induces LMP, disrupts mitophagic flux, and causes mitochondrial dysfunction in NP cells. IL‐1β enhances WTAP, a key part of the m6A methyltransferase complex, essential for m6A methylation of ACSL4 mRNA. The m6A reader IGF2BP2 then binds and stabilizes the modified transcripts, leading to increased ACSL4 expression. Consequently, lysosomal lipid peroxidation is promoted through accumulation of arachidonic acid‐containing phospholipids, resulting in LMP. In a rat model, intradiscal delivery of AAV9‐shWTAP attenuates disc degeneration, with preserved disc height, improved extracellular matrix synthesis, and restored lysosomal function and mitophagy. Our study reveals the WTAP/ACSL4/IGF2BP2 axis as a mediator of IL‐1β‐induced LMP via m6A‐dependent lipid peroxidation, highlighting a potential therapeutic target for IVDD.
Shu Jia, Xu Gao, Laimin Zhu et al.· Advancement of science· 0 citations
Multiple sclerosis is characterized by immune-mediated demyelination and inefficient remyelination, owing to impaired differentiation of oligodendrocyte precursor cells (OPCs) into myelinating oligodendrocytes (OLs). Inflammatory cytokines within multiple sclerosis lesions inhibit OPC maturation and induce an immune-like phenotype with antigen-presenting properties, but the underlying mechanisms remain poorly defined. Here, we show that inflammation reprograms OPC lipid metabolism, linking altered metabolism to remyelination failure. In cultured rodent OPCs, interferon-γ (IFN-γ) induced a switch from lipid synthesis to utilization, leading to reduced intracellular fatty acid levels and increased dependence on fatty acid oxidation. Transcriptional analyses confirmed similar lipid metabolic changes in OL-lineage cells cultured from human surgical specimens or isolated from mouse models of inflammatory demyelination and human multiple sclerosis lesions. Enhancing lipid availability in OPCs through oleic acid supplementation or inhibition of fatty acid oxidation attenuated immune-like functions and increased differentiation. Pharmacologic activation of liver X receptor (LXR) transcription factors rebalanced lipid metabolism, suppressed immune-like functions, and overcame IFN-γ–induced differentiation blockade in both mouse and human-derived OPCs. In an adoptive transfer-cuprizone mouse model in which inflammation directly impairs remyelination, LXR activation increased mature OL generation and augmented myelin repair. Together, these findings identify lipid metabolic remodeling as a key mechanism by which inflammation impairs OPC differentiation and highlight LXR activation as a therapeutic approach to enhance remyelination in multiple sclerosis.
Judy J Lee, Matthew D. Smith, Xiaojing Deng et al.· bioRxiv· 0 citations
Psoriasis is a chronic inflammatory skin disorder in which biologics targeting immune pathways have markedly improved clinical outcomes. Nevertheless, persistent oxidative stress and stromal abnormalities in lesional skin indicate that pathogenic mechanisms beyond canonical immune circuits remain active. Here, we integrated single‐cell RNA sequencing, an imiquimod (IMQ)‐induced psoriasiform murine model, LC–MS/MS‐based metabolomic profiling of fibroblast‐conditioned medium, and complementary in vitro studies to define ferroptosis‐related alterations in dermal fibroblasts under psoriasis‐like inflammatory conditions. Single‐cell analysis revealed a marked expansion of an inflammatory fibroblast subset (iFb1) in psoriasiform lesions, together with enrichment of ferroptosis‐related pathways. In vivo and in vitro analyses further showed that inflammatory stimulation induced ferroptosis‐related injury in dermal fibroblasts, as evidenced by increased lipid peroxidation, impaired antioxidant defenses, and characteristic ultrastructural alterations. Metabolomic profiling of conditioned medium further indicated secretory remodeling characterized by enrichment of lipid mediators and redox‐associated metabolites. Lipocalin‐2 (LCN2) was significantly upregulated in psoriasis‐associated fibroblasts and exacerbated lipid peroxidation and ferroptosis‐related injury. Conditioned medium from inflammation‐stimulated fibroblasts enhanced keratinocyte proliferation, whereas inhibition of fibroblast ferroptosis or LCN2 knockdown attenuated this effect. Further experiments suggested that 4‐hydroxy‐2‐nonenal (4‐HNE) may act as a potential mediator of fibroblast–keratinocyte crosstalk. Topical administration of carnosine, a potent 4‐HNE scavenger, alleviated IMQ‐induced psoriasiform skin lesions in vivo. Together, these findings support an LCN2‐driven fibroblast–keratinocyte crosstalk axis linked to ferroptosis‐related injury in psoriasis and highlight stromal lipid peroxidation as a potential therapeutic target.
Min Zhang, GuangDong Liu, Shu-Xin Wang et al.· The FASEB Journal· 0 citations
Atherosclerotic cardiovascular disease, a chronic inflammatory disorder, remains the leading cause of death globally. Macrophages (Møs) promote inflammation resolution and atherosclerosis regression by eating up apoptotic cells via efferocytosis. This imposes a metabolic burden on Møs that requires the efficient catabolism of lipids derived from efferocytic cargoes for effective pro-resolving responses and plaque stability. Our data suggest that lipin-1 attenuates atherosclerosis and promotes inflammation resolution by enhancing mitochondrial oxidative phosphorylation (OXPHOS) and efferocytosis. However, the mechanism by which lipin-1 aids OXPHOS and efferocytosis in pro-resolving macrophages is unknown. Therefore, we hypothesize that lipin-1 drives these processes by facilitating cardiolipin synthesis.
We used flow cytometry, fluorescence microscopy, mass spectrometry and RNA interference to assess cardiolipin levels and their impact on efferocytosis in lipin-1 knockout (lipin-1 KO) and wildtype (WT) bone marrow-derived Møs. Also, mitochondrial-ER contact sites (MERCs) formation in WT and lipin-1 KO Mø was observed by electron microscopy.
Lipin-1 KO Møs had a significant reduction in cardiolipin, a mitochondria-exclusive phospholipid critical for mitochondrial structure and OXPHOS. Reducing cardiolipin synthesis in WT Møs significantly impaired their efferocytic capacity. Also, in response to IL-4, lipin-1 KO Møs exhibited significantly fewer MERCs. MERCs regulate the transfer of lipid precursors essential for cardiolipin synthesis in the mitochondria.
Our findings show that lipin-1 aids MERCs formation and cardiolipin synthesis to support macrophage efferocytosis and pro-resolving responses. This deepens our insight into the cellular and molecular mechanisms driving inflammation resolution and atherosclerosis regression, which may inform future studies on metabolic regulation of immune responses in chronic inflammation.
1. NIH under grant number P20GM134974 and R01HL163106, 2. CCDS under grant number CCDS000013, 3. AHA predoctoral fellowship under grant number 25PRE1373728
Innate Immune Responses and Host Defense: Molecular Mechanisms (INM)
Oluwakemi O. Igiehon, Temitayo T. Bamgbose, Robert M. Schilke et al.· Journal of Immunology· 0 citations
Atherosclerosis is driven by the interplay between lipid accumulation, chronic inflammation, and macrophage dysfunction. Although intensive lipid-lowering therapy reduces cardiovascular risk, substantial residual risk persists, highlighting the importance of impaired macrophage cholesterol handling and reverse cholesterol transport (RCT). This review summarizes the bidirectional relationships between macrophage programmed cell death and cholesterol metabolism, with a focus on apoptosis, pyroptosis, necroptosis, and ferroptosis, which have been comparatively well studied in atherosclerosis and have direct or indirect links to macrophage cholesterol handling. Apoptosis may support plaque homeostasis when apoptotic cells are efficiently cleared by efferocytosis, thereby limiting inflammation and promoting LXR-dependent cholesterol efflux. In contrast, defective efferocytosis can lead to secondary necrosis and inflammatory amplification. Pyroptosis, necroptosis, and ferroptosis may impair macrophage cholesterol homeostasis through overlapping mechanisms involving inflammatory signaling, oxidative stress, membrane disruption, reduced ABCA1/ABCG1-dependent efflux, and HDL dysfunction. Autophagy and lipophagy exert context-dependent effects: appropriate autophagic flux facilitates intracellular cholesterol mobilization, whereas excessive or dysregulated autophagy may increase ferroptotic susceptibility through ferritinophagy, iron release, and GPX4 loss. Based on these observations, we propose a macrophage death-mode bifurcation framework centered on caspase-8 activity, RIPK1 ubiquitination, mitochondrial stress, oxidative stress thresholds, and autophagic flux. These interconnected nodes may influence whether macrophages undergo apoptosis with efficient clearance or inflammatory and lytic death associated with impaired net cholesterol flux. However, the strength of evidence differs among death modalities, and many proposed links remain indirect or primarily supported by preclinical studies. This framework provides a basis for future studies integrating cell-death regulation, cholesterol transport, and plaque stability.
Yanan Bian, Xiaoyang Hu· Frontiers in Cardiovascular...· 0 citations
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