Interaction Between Macrophages and Ferroptosis: Metabolism, Function, and Diseases

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Interaction Between Macrophages and Ferroptosis: Metabolism, Function, and Diseases

Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a critical player in various pathological processes. Macrophages, versatile immune cells with diverse metabolic functions, interact intricately with ferroptosis, influencing tissue homeostasis and disease progression. This review elucidates the mechanisms underlying ferroptosis, its regulation by macrophage metabolism, and the bidirectional relationship between ferroptotic processes and macrophage functions in health and disease.

Mechanisms and Regulation of Ferroptosis

Ferroptosis is characterized by the accumulation of reactive oxygen species (ROS), iron overload, and peroxidation of polyunsaturated fatty acids (PUFAs) in cellular membranes. Three core metabolic pathways regulate ferroptosis: iron metabolism, lipid metabolism, and redox systems.

Iron Metabolism

Iron, particularly labile Fe²⁺, catalyzes the Fenton reaction, generating hydroxyl radicals (·OH) that oxidize PUFAs. Cellular iron homeostasis is maintained through:

  • Iron uptake via transferrin receptor 1 (TFRC), divalent metal transporter 1 (DMT1), and Zrt-/Irt-like proteins (ZIP8/14).
  • Iron storage in ferritin complexes (FTH/FTL), which sequester Fe³⁺.
  • Iron export via ferroportin (FPN), regulated by hepcidin.
    Disruption of iron balance—such as increased uptake, impaired storage (e.g., NCOA4-mediated ferritinophagy), or reduced export—promotes ferroptosis.

Lipid Metabolism

PUFAs in membrane phospholipids (PL-PUFAs) are primary targets of peroxidation. Enzymes like acyl-CoA synthase 4 (ACSL4) and lysophosphatidylcholine acyltransferase 3 (LPCAT3) incorporate PUFAs into membranes, while lipoxygenases (ALOXs), cyclooxygenases (COXs), and cytochrome P450 oxidases (CYP450) catalyze their oxidation. Conversely, monounsaturated fatty acids (MUFAs) incorporated by ACSL3 inhibit ferroptosis by reducing lipid peroxidation susceptibility.

Redox Systems

Antioxidant systems counteract lipid peroxidation:

  1. GPX4-GSH pathway: Glutathione peroxidase 4 (GPX4) reduces lipid hydroperoxides using glutathione (GSH), synthesized from cysteine imported via system Xc⁻ (SLC7A11/SLC3A1).
  2. FSP1-CoQ10 pathway: Ferroptosis suppressor protein 1 (FSP1) regenerates ubiquinol (CoQ10H₂), a lipid-soluble antioxidant.
  3. GCH1-BH4 pathway: GTP cyclohydrolase-1 (GCH1) produces tetrahydrobiopterin (BH4), which stabilizes CoQ10 and directly scavenges radicals.

Macrophage Metabolism and Ferroptosis

Macrophages regulate systemic and local iron, lipid, and redox balance, impacting ferroptosis in neighboring cells while resisting ferroptosis themselves through specialized mechanisms.

Iron Metabolism in Macrophages

Macrophages phagocytose senescent erythrocytes and recycle heme via CD163, CD91, and HRG1. Intracellular heme is degraded by heme oxygenase-1 (HO-1) into Fe²⁺, biliverdin, and carbon monoxide (CO). Key adaptations protect macrophages from iron toxicity:

  • Spi-C transcription factor upregulates FPN to enhance iron export.
  • HO-1 activity limits Fe²⁺ accumulation and generates bilirubin/CO, which inhibit ROS and NOX enzymes.
  • Ferritin storage and non-classical secretion of ferritin-containing exosomes reduce intracellular iron load.

Macrophages also modulate tissue iron levels. For example, cardiac macrophages clear heme after injury, while microglia sequester iron to protect neurons. Conversely, hepatic macrophages release lactoferrin-rich extracellular traps to induce hepatocyte ferroptosis during ischemia-reperfusion.

Lipid and Redox Metabolism

Macrophages internalize oxidized low-density lipoprotein (oxLDL), leading to lipid peroxidation and foam cell formation. Pathogen-associated molecular patterns (PAMPs) activate Toll-like receptors (TLRs), triggering ROS production via NADPH oxidases (NOXs) and mitochondrial pathways. While ROS aid pathogen killing, macrophages mitigate self-damage by compartmentalizing ROS in phagolysosomes and upregulating antioxidants (e.g., SOD2, AIFM1). Nitric oxide (NO·) from inducible nitric oxide synthase (iNOS) inhibits ferroptosis by competing with ALOX15B for catalytic sites and activating Nrf2.

Ferroptosis and Macrophage Functions

Macrophage Recruitment and Activation

Ferroptotic cells release damage-associated molecular patterns (DAMPs), such as HMGB1 and ATP, which recruit macrophages via AGER and chemokines (CCL2, CCL17). Ferroptosis in renal tubular cells or endothelial cells amplifies inflammation by activating NLRP3 inflammasomes and NF-κB in macrophages. Conversely, macrophage-derived itaconate suppresses ferroptosis by enhancing Nrf2 and GPX4.

Macrophage Polarization

M1 macrophages exhibit high ferroptotic stress but resist death due to:

  • Compartmentalized ROS in phagosomes.
  • Fe²⁺ export via FPN.
  • NO·-mediated inhibition of ALOX15B.
    M2 macrophages, reliant on GPX4, are ferroptosis-sensitive. Ferroptosis inducers (e.g., RSL3) shift macrophages toward pro-inflammatory M1 phenotypes, while ACSL4 knockdown reduces TNF-α and IL-6 production.

Phagocytosis and Pathogen Clearance

During early infection, transient Fe²⁺ accumulation and ROS enhance bacterial killing. However, excessive ferroptosis (e.g., in Mycobacterium tuberculosis-infected macrophages) causes pathogen release. Oxidized PL-PUFAs on ferroptotic cells act as “eat-me” signals, engaging TLR2 on macrophages for clearance.

Tumor Microenvironment

M2-polarized tumor-associated macrophages (TAMs) secrete CXCL8 and miR-660-5p to inhibit ferroptosis in endothelial and cancer cells. Conversely, ferroptotic tumor cells recruit M1 TAMs via DAMPs, promoting antitumor immunity.

Macrophage Ferroptosis in Disease

Infections

Pathogens like M. tuberculosis and Staphylococcus aureus induce macrophage ferroptosis to evade immune clearance. Inhibiting ferroptosis (e.g., via HO-1 upregulation) reduces bacterial dissemination.

Neurological Disorders

Microglial ferroptosis contributes to Parkinson’s disease and multiple sclerosis. Iron overload in microglia initially protects neurons but eventually triggers neuronal death. M1 microglia resist ferroptosis via NO·, while M2 microglia are vulnerable.

Atherosclerosis

oxLDL uptake by macrophages promotes ferroptosis, releasing inflammatory cytokines (IL-1β, TNF-α) and metalloproteinases (MMP-2/9) that destabilize plaques. HIF-1α inhibition or Sirtuin1 activation attenuates ferroptosis, reducing lesion progression.

Osteoporosis and Osteoarthritis

Osteoclast ferroptosis is inhibited by HIF-1α under hypoxia, promoting bone resorption. In osteoarthritis, mesenchymal stem cell exosomes inhibit macrophage ferroptosis via Nrf2/HO-1, preserving cartilage.

Cancer

Asbestos-induced macrophage ferroptosis releases iron-rich vesicles that cause DNA damage in mesothelial cells, driving mesothelioma. In hepatocellular carcinoma, TMEM147 promotes M2 polarization and ferroptosis resistance.

Therapeutic Strategies

  1. Inhibiting ferroptosis and inflammation: Nrf2 activators (e.g., sulforaphane) and NO· donors block lipid peroxidation.
  2. Enhancing macrophage resistance: HO-1 inducers and ferritinophagy inhibitors (e.g., liensinine) protect macrophages in sepsis or liver injury.

Conclusions and Future Directions

The interplay between macrophages and ferroptosis spans metabolic regulation, immune function, and disease pathogenesis. Key unanswered questions include:

  1. Thresholds separating physiological macrophage functions from pathological ferroptosis.
  2. Tissue-specific differences in macrophage-ferroptosis interactions.
  3. Therapeutic targeting of macrophage ferroptosis in non-cancer diseases.

Advancing single-cell omics and iron/lipid peroxidation sensors will clarify spatiotemporal regulation. Harnessing macrophage plasticity to modulate ferroptosis offers promise for treating infections, neurodegeneration, and inflammatory disorders.

doi.org/10.1097/CM9.0000000000003189

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