In sickle cell disease (SCD), free heme associated with hemolysis leads to altered macrophage functional properties, resulting in defective efferocytosis and exacerbating the inflammatory response to tissue damage, according to research published in Blood.
The study demonstrated that restoration of macrophage function via heme scavengers or PGC1α/PPARγ modulation represents a potential therapeutic strategy to prevent aggravated tissue damage, persistent inflammation, and autoimmunity in SCD.
Researchers investigated the mechanisms underlying heme-mediated defective efferocytosis and alteration of macrophage functional properties, including apoptotic cell efferocytosis, mitochondrial dynamics, and metabolic shifts.
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Using murine models of SCD, they showed that heme exposure alters macrophage functional response to apoptotic cell damage by stimulating excessive inflammatory cell recruitment. This alteration led to defective efferocytosis, which exacerbated tissue damage and sustained inflammation.
Mechanistic studies of bone marrow–derived macrophages of SCD models demonstrated that heme activated TLR4 signaling and suppressed the transcription factor PPARγ (proliferator-activated receptor γ) and its coactivator PGC1α (peroxisome proliferator-activated receptor γ coactivator 1α).
The reduction of PGC1α/PPARγ expression led to impaired mitochondrial biogenesis and dynamics. Further experiments showed heme-exposed macrophages were unable to undergo an efferocytosis-induced metabolic switch to fatty acid β-oxidation and ATP production and reduced secretion of the antiinflammatory cytokines interleukin-4 (IL-4) and IL-10.
When heme-exposed bone marrow–derived macrophages were treated with heme scavengers or PGC1α/PPARγ modulation, the treatment counteracted inflammation and improved tissue damage resolution through restored apoptotic cell clearance.
The researchers also demonstrated that bone marrow–derived macrophages exposed to the plasma of patients with SCD had impaired phagocytic capacity, which was improved by treatment with heme scavengers, PPARγ agonists, or IL-4.
“Overall, our results show that, beyond sterile inflammation, hemolysis is a driver of exacerbated immune cell recruitment, defective efferocytosis, impaired resolution of inflammation, and tissue damage. This has major implications for SCD, in which the restoration of homeostasis after vaso-occlusion-induced ischemic damage is counteracted by the presence of heme excess,” concluded the researchers. “Our findings demonstrate that macrophage functional rewiring has therapeutic benefit for the amelioration of tissue damage and inflammation and the prevention of autoimmune diseases in SCD.”
Disclosure: One study author declared affiliations with biotech, pharmaceutical, or device companies. Please see the original reference for a full list of authors’ disclosures.
Reference
Sharma R, Antypiuk A, Vance SZ, et al. Macrophage metabolic rewiring improves heme-suppressed efferocytosis and tissue damage in sickle cell disease. Blood. 2023;141(25):3091-3108. doi:10.1182/blood.2022018026
