Free Heme Impairs Macrophage Function and Exacerbates Tissue Damage in Sickle Cell Disease

New research published in the journal Blood has found that sickle cell disease (SCD) leads to altered macrophage function due to heme associated with hemolysis. This alteration results in defective efferocytosis and worsens the inflammatory response to tissue damage. Researchers suggest that restoring macrophage function through heme scavengers or PGC1α/PPARγ modulation could be a potential therapeutic strategy to prevent persistent inflammation, aggravated tissue damage, and autoimmunity in SCD.

In the study, murine models of SCD were used to investigate the mechanisms behind heme-mediated defective efferocytosis and changes in macrophage function. The exposure to heme altered the response of macrophages to apoptotic cell damage, leading to excessive inflammatory cell recruitment and defective efferocytosis. This not only exacerbated tissue damage but also sustained inflammation. Mechanistic studies revealed that heme activation of TLR4 signaling suppressed the transcription factor PPARγ and its coactivator PGC1α, which impaired mitochondrial dynamics and biogenesis. Heme-exposed macrophages were unable to switch to fatty acid β-oxidation and ATP production, resulting in reduced anti-inflammatory cytokine secretion. However, when heme-exposed macrophages were treated with heme scavengers or through PGC1α/PPARγ modulation, inflammation was counteracted, tissue damage resolution was improved, and apoptotic cell clearance was restored.

The research also showed that patient plasma impaired the phagocytic capacity of bone marrow-derived macrophages, which improved with treatment using heme scavengers, PPARγ agonists, or interleukin-4 (IL-4). The results demonstrate the potential therapeutic benefit of restoring macrophage function in SCD to ameliorate tissue damage, inflammation, and autoimmune diseases.