Escaping the traps of your own hunters

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Science  01 Dec 2017:
Vol. 358, Issue 6367, pp. 1126-1127
DOI: 10.1126/science.aar2428

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During the first days of an infection, protection is almost entirely provided by innate immunity, a large part of which consists of one type of immune cell—the neutrophil. Neutrophils form the largest group of immune cells in the body [humans produce ∼1011 neutrophils daily (1)], and they carry out a number of defense mechanisms, including pathogen ingestion (phagocytosis) and the production of toxic chemicals that kill intruders directly. They can also cause severe hyperinflammatory diseases, such as lethal influenza-associated lung destruction (2, 3). In 2004, another neutrophil defense system was discovered. In a final act of protection, dying neutrophils mix their nuclear DNA with toxic components from their cytosolic granules and release it explosively to form a neutrophil extracellular trap (NET) in the surrounding environment. This process is called NETosis (4). In addition to carrying genetic information, DNA is a very long (each nucleus contains ∼2 m of DNA) and sticky polyanionic molecule. Hence, DNA binds to surfaces such as bacterial cell walls by means of charge interactions (5). Through this immobilization on NETs, pathogens are brought into direct contact with cytotoxic molecules on the NET-DNA complex. However, free extracellular DNA is also a potent trigger of severe side effects in the body, for example, by forming immune complexes with anti nuclear antibodies (antibodies that can bind to DNA) in systemic lupus erythematosus (SLE) (6) or by directly clogging blood vessels and establishing vessel-blocking thrombi (7). Consequently, finding mechanisms that mediate the degradation of NETs has been a matter of intense research. On page 1202 of this issue, Jiménez-Alcázar et al. (8) describe two deoxyribonucleases (DNases) [DNase1 and DNase1-like 3 (DNase1L3)], which cleave DNA and together degrade freshly formed NETs. By doing so, they inhibit otherwise lethal immunopathologies such as thrombus-mediated organ failure.