Macrophage extracellular trap formation promoted by platelet activation is a key mediator of rhabdomyolysis-induced acute kidney injury

Nat Med. 2018 Feb;24(2):232-238. doi: 10.1038/nm.4462. Epub 2018 Jan 8.


Rhabdomyolysis is a serious syndrome caused by skeletal muscle injury and the subsequent release of breakdown products from damaged muscle cells into systemic circulation. The muscle damage most often results from strenuous exercise, muscle hypoxia, medications, or drug abuse and can lead to life-threatening complications, such as acute kidney injury (AKI). Rhabdomyolysis and the AKI complication can also occur during crush syndrome, an emergency condition that commonly occurs in victims of natural disasters, such as earthquakes, and man-made disasters, such as wars and terrorism. Myoglobin released from damaged muscle is believed to trigger renal dysfunction in this form of AKI. Recently, macrophages were implicated in the disease pathogenesis of rhabdomyolysis-induced AKI, but the precise molecular mechanism remains unclear. In the present study, we show that macrophages released extracellular traps (ETs) comprising DNA fibers and granule proteins in a mouse model of rhabdomyolysis. Heme-activated platelets released from necrotic muscle cells during rhabdomyolysis enhanced the production of macrophage extracellular traps (METs) through increasing intracellular reactive oxygen species generation and histone citrullination. Here we report, for the first time to our knowledge, this unanticipated role for METs and platelets as a sensor of myoglobin-derived heme in rhabdomyolysis-induced AKI. This previously unknown mechanism might be targeted for treatment of the disease. Finally, we found a new therapeutic tool for prevention of AKI after rhabdomyolysis, which might rescue some sufferers of this pathology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Kidney Injury / etiology
  • Acute Kidney Injury / genetics*
  • Acute Kidney Injury / pathology
  • Animals
  • Citrullination / genetics
  • Crush Syndrome / etiology
  • Crush Syndrome / genetics*
  • Crush Syndrome / pathology
  • DNA / genetics
  • DNA / metabolism
  • Disease Models, Animal
  • Extracellular Traps / genetics
  • Extracellular Traps / metabolism
  • Heme / metabolism
  • Histones / metabolism
  • Humans
  • Macrophages / metabolism
  • Macrophages / pathology
  • Mice
  • Muscle, Skeletal / injuries
  • Muscle, Skeletal / pathology
  • Myoglobin / genetics
  • Platelet Activation / genetics*
  • Reactive Oxygen Species / metabolism
  • Rhabdomyolysis / complications
  • Rhabdomyolysis / genetics*
  • Rhabdomyolysis / pathology
  • Secretory Vesicles / genetics


  • Histones
  • Myoglobin
  • Reactive Oxygen Species
  • Heme
  • DNA