The kidney gets caught in a macrophage trap

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Science Immunology  02 Mar 2018:
Vol. 3, Issue 21, eaat3745
DOI: 10.1126/sciimmunol.aat3745


Myogloblin released from dead muscle is shown to induce acute kidney injury through a mechanism dependent on platelets and macrophage extracellular traps.

In rhabdomyolysis muscle necrosis leads to the leakage of myoglobin, a protein-heme complex, into the blood. Myoglobin is readily excreted by the kidney, but the heme component is highly toxic to renal tubule cells. As a result, acute kidney injury leading to renal failure is a major cause of morbidity and mortality in the setting of severe muscle trauma. The mechanism of heme-induced kidney injury is unknown, although recent work has implicated macrophages and reactive oxygen species (ROS). Okubo and colleagues now show that renal injury in the setting of muscle necrosis is caused by myoglobin-induced extracellular traps (ETs) released from macrophages. It is well known that neutrophils contribute microbial defense and to various disease processes by extruding DNA-histone fibers with attached granule contents, so-called neutrophil extracellular traps or “NETs.” A few recent reports have indicated that macrophages can also release extracellular traps (METs), but the pathophysiological significance of METs is not known. In a mouse model of intramuscular glycerol injection to induce rhabdomyolysis, Okubo et al. observed ET formation and macrophage infiltration in renal tubules within 8 hours after the injection, correlating with impaired renal function. They also show that peptidyl arginine deiminase type IV, which catalyzes histone citrullination and is required for NET formation, is required for kidney damage in mouse rhabdomyolysis. Deoxyribonuclease treatment of mice reduced rhabdomyolysis-associated renal damage, without affecting muscle damage. Notably, monoclonal antibody–mediated depletion of macrophages or platelets, but not neutrophils, substantially reduced renal injury and plasma DNA after muscle injury. Lactoferrin treatment of mice with rhabdomyolysis prevented renal damage, elevation of plasma DNA, and MET formation. Other experiments in mice and cultured human macrophages indicated that heme induction of METs occurs via activation of platelets binding to the integrin Mac-1 on macrophages, which leads to ROS generation. This paper establishes the relevance of METs in human disease and points to MET formation as a therapeutic target to prevent renal injury following muscle necrosis. Several questions remain unanswered, such as how heme activates platelets, the location of the platelet-macrophage interactions, and the components of the METs that are toxic to renal tubule cells.

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