Macrophage metabolic rewiring counteracts inflammation and improves tissue damage resolution by restoring heme-suppressed AC clearance. (A) Levels of TNFα, IL-6, interferon gamma (IFN-γ), IL-4, and IL-10 monitored by flow cytometry in BMDMs exposed or not to ACs (1 BMDM to 0.5 AC ratio) in presence of 5 μM heme-albumin (heme) without or with 1 μM Pio or 50 ng/mL IL-4 for 6 hours (i). Levels of TNFα, IFN-γ, IL-4, and IL-10 monitored by flow cytometry in KCs of HbA mice and HbS mice untreated or receiving IL-4 or Pio treatment (ii). Protein levels are expressed in MFI as fold change to control BMDMs. (B) Outline of in vivo experiment on hepatotoxicity induced by thioacetamide (TAA) in Wt mice. Parameters were monitored at days 1 and 4 after TAA treatment (i). Percentage of efferocytic ASPGR⁺ resident and recruited phagocytes (day 1) in the liver of Wt mice untreated or treated with TAA alone (100 mg/kg TAA) or combined with heme (70 μmol/kg heme) or heme/Pio (10 mg/kg per day Pio) (ii). Expression level of efferocytic receptors (TIM4, MerTk, CD36, CD206, MARCO, CD169) in KCs of Wt mice treated with TAA alone or combined with heme or heme/Pio (iii). Percentage of annexin V⁺ and caspase-3⁺ apoptotic CD45⁻ hepatic parenchymal cells (iv) and representative images of hematoxylin/eosin staining on liver sections of Wt mice treated with TAA alone or combined with heme or heme/Pio (v). Damaged apoptotic/necrotic areas are highlighted in the pictures by the yellow dashed line. AST activity and antinuclear antibody activity in sera of Wt mice treated with TAA alone or combined with heme or heme/Pio (vi,vii). Protein expression levels are expressed in MFI as fold change to TAA-treated mice. Data show a representative of 2 independent experiments. Values represent mean ± SEM. Statistical analysis was performed by comparing 3 or more groups with a 1-way ANOVA followed by a Bonferroni posttest. ∗P < .05; ∗∗P < .01; ∗∗∗P < .001; ∗∗∗∗P < .0001.