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Jun 24, 2014

Even after Cell Death, the Inflammasome Has “Not Yet Begun to Fight”

Even after Cell Death, the Inflammasome Has “Not Yet Begun to Fight”

Macrophages containing activated inflammasomes. Note redistribution of ASC molecules (green) to form ASC specks (green fibrillar structures). Blue: nuclei; Red: plasma membranes. [Eicke Latz/Uni Bonn]

  • With the resolve of a subcellular John Paul Jones, the inflammasome continues to drive inflammatory reactions even after the cell in which is expressed is effectively sunk. In living immune cells, the inflammasome, a large multiprotein complex, forms when the cell is under stress and activates an enzyme, caspase-1, which induces maturation of the cytokine interleukin 1β.

    The resulting inflammatory reaction actually induces pyroptotic cell death. That, you might think, would take the inflammasome out of the fray. But the inflammasome, refusing to go down with the ship, keeps fighting. It activates additional messengers and promotes further cytokine maturation. In addition, phagocytosis of inflammasomes by macrophages induces lysosomal damage and nucleation of soluble inflammasomes, as well as activation of interleukin 1β in recipient cells.

    These findings, which suggest a new form of cell-to-cell communication, were established by scientists based at the Institute of Innate Immunity at the University Hospital of Bonn. These scientists used fluorescence techniques to track inflammasomes via ASC specks.

    Inflammasomes require the adapter protein apoptosis associated speck-like protein containing a CARD (ASC) for the activation of caspase-1. After inflammasome activation, ASC assembles into a large protein complex, the so-called speck.

    The scientists contrived to label inflammasomes so that they would, upon activation, form a fluorescent protein complex reminiscent of small stars glowing inside the cell. Using this method, the scientists were able to track the inflammasome after cell death, and show that it remained switched on as an intact protein complex. They also found that once released from the dead cell, it stimulated neighboring cells to undergo an inflammatory reaction. Furthermore, they found that these extracellular complexes accumulate in the lungs of patients with chronic lung disease.

    These findings appeared June 22 in Nature Immunology, in an article entitled “The adaptor ASC has extracellular and 'prionoid' activities that propagate inflammation.” They offer potentially novel approaches for therapies against many serious diseases.

    “Normally, the immune system is very helpful for averting harmful damage to tissue by initiating an inflammatory reaction,” said Prof. Eicke Latz, the director of the Institute of Innate Immunity. However, if such inflammatory reactions are excessive or if they persist for longer than necessary, this may contribute to common diseases such as gout, Alzheimer’s disease, diabetes, or atherosclerosis. (Inflammasomes are activated by cellular stresses such as detection of microbes, deposition of uric acid cystals in joints, of the accumulation of cholesterol in blood vessels or Alzheimer's plaques in the brain.)

    With the discovery of extracellular inflammasomes, the researchers have revealed an interesting avenue for potential new therapies: “If we are able to produce suitable antibodies, it is likely we could contain the alarm of the inflammasome outside of cells and thus keep harmful chronic inflammatory reactions at bay, without affecting the necessary response inside the cell,” concluded Prof. Latz.


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