Franklin BS, Bossaller L, De Nardo D, Ratter JM, Stutz A, Engels G, Brenker C, Nordhoff M, Mirandola SR, Al-Amoudi A, Mangan MS, Zimmer S, Monks BG, Fricke M, Schmidt RE, Espevik T, Jones B, Jarnicki AG, Hansbro PM, Busto P, Marshak-Rothstein A, Hornemann S, Aguzzi A, Kastenmüller W, Latz E. The adaptor ASC has extracellular and 'prionoid' activities that propagate inflammation. Nat Immunol. 2014 Aug;15(8):727-37. Epub 2014 Jun 22 PubMed.

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  1. These two recent papers in Nature Immunology provide clear evidence that an intracellular protein complex known as the inflammasome can actually be released from the cell after activation. This is potentially relevant in the context of neurodegenerative disease, as one particular inflammasome complex, regulated by the protein NLRP3, is thought to contribute to the progression of Alzheimer's, amyotrophic lateral sclerosis, and other neuroinflammatory conditions.

    In the context of infection, this protein complex is very important for inflammation that can defeat pathogens, however, it is somehow being activated inappropriately in the context of neurodegeneration. These new findings show that not only does the initial cell that gets activated produce inflammatory cytokines, but that the actual protein complex itself is released, propagating inflammation in nearby cells, and also systemically.

    This discovery now provides a rationale for therapies that could shut down this amplification of inflammation, because previously it was not possible to target the intracellular protein complex with neutralising antibodies. However, preliminary studies in this paper show that using the wrong type of antibodies to target this extracellular protein complex does not actually neutralise it, and instead it can promote uptake and actually increase inflammation. Fortunately, the technology exists to develop antibodies that will not be taken up in this manner, and it should be possible to neutralize this pathway in the near future.

    View all comments by Seth Masters

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