Acute Hemolysis and Heme Suppress Anti-CD40 Antibody-Induced Necro-Inflammatory Liver Disease

Abstract

Clearance of red blood cells and hemoproteins is a key metabolic function of macrophages during hemolytic disorders and following tissue injury. Through this archetypical phagocytic function, heme is detoxified and iron is recycled to support erythropoiesis. Reciprocal interaction of heme metabolism and inflammatory macrophage functions may modify disease outcomes in a broad range of clinical conditions. We hypothesized that acute hemolysis and heme induce acute anti-inflammatory signals in liver macrophages. Using a macrophage-driven model of sterile liver inflammation, we showed that phenylhydrazine (PHZ)-mediated acute erythrophagocytosis blocked the anti-CD40 antibody-induced pathway of macrophage activation. This process attenuated the inflammatory cytokine release syndrome and necrotizing hepatitis induced by anti-CD40 antibody treatment of mice. We further established that administration of heme-albumin complexes specifically delivered heme to liver macrophages and replicated the anti-inflammatory effect of hemolysis. The anti-inflammatory heme-signal was induced in macrophages by an increased intracellular concentration of the porphyrin independently of iron. Overall, our work suggests that induction of heme-signaling strongly suppresses inflammatory macrophage function, providing protection against sterile liver inflammation.

Engineered Nanoerythrocytes Alleviate Central Nervous System Inflammation by Regulating the Polarization of Inflammatory Microglia

“…However, once released from cells and hemeproteins, free heme can activate specific receptors on the surface of immune cells such as TLR4, causing oxidative damage and inflammation. [ 15 ] When heme is transported into cells, heme‐induced HO‐1, CO, and bilirubin production promote healing and repair of myocardial infarction, [ 26 ] necro‐inflammatory liver disease, [ 27 ] and atherosclerosis. [ 28 ] Heme has an anti‐inflammatory effect in cells, a possible mechanism being that heme signaling enhances intracellular porphyrin concentration.…”

“…[ 28 ] Heme has an anti‐inflammatory effect in cells, a possible mechanism being that heme signaling enhances intracellular porphyrin concentration. [ 27 ] Therefore, HO‐1 regulation by heme is an essential feedback mechanism that degrades intracellular heme, exerting antioxidant and anti‐inflammatory cytoprotective effects. [ 15a ]…”

“…[28] Heme has an anti-inflammatory effect in cells, a possible mechanism being that heme signaling enhances intracellular porphyrin concentration. [27] Therefore, HO-1 regulation by heme is an essential feedback mechanism that degrades intracellular heme, exerting antioxidant and anti-inflammatory cytoprotective effects. [15a] Compared with free heme, the engineered nanoerythrocyte constructed in this study was efficiently and accurately delivered to inflammatory microglia to play a regulatory role, directly activating intracellular HO-1, enhancing the Notch1/Hes1/Stat3 signaling pathway and inhibiting NF-κB p65 nuclear translocation.…”

“…[15a] Compared with free heme, the engineered nanoerythrocyte constructed in this study was efficiently and accurately delivered to inflammatory microglia to play a regulatory role, directly activating intracellular HO-1, enhancing the Notch1/Hes1/Stat3 signaling pathway and inhibiting NF-κB p65 nuclear translocation. Therefore, it effectively prevents free heme from activating toll-like receptors (such as TLR4) on the surface of immune cells such as macrophages, microglia, and white blood cells, [27] thus effectively avoiding the pro-inflammatory effect and exerting the anti-inflammatory effect.…”

Hemolysis, free hemoglobin toxicity, and scavenger protein therapeutics

“…Heme signaling profoundly impairs the antigen presentation capacity and innate immune functions of erythrophagocytes. This process is accompanied by the downregulation of MHC class 2 expression and suppressed NF-κB activation subsequent to TLR4 or CD40 ligation 44,46,56 . Although this immunoregulatory function of heme can cause immunodeficiency in hemolytic anemia, it likely evolved as a protective mechanism against harmful inflammation and development of autoimmunity during wound healing.…”