A SerpinBl Regulatory Mechanism Is Essential for Restricting Neutrophil Extracellular Trap Generation.

NETosis (neutrophil extracellular trap [NET] generation), a programmed death pathway initiated in mature neutrophils by patho-gens and inflammatory mediators, can be a protective process that sequesters microbes and prevents spread of infection, but it can also be a pathological process that causes inflammation and serious tissue injury. Little is known about the regulatory mechanism. Previously, we demonstrated that serpinbl-deficient mice are highly susceptible to pulmonary bacterial and viral infections due to inflammation and tissue injury associated with increased neutrophilic death. In this study, we used in vitro and in vivo approaches to investigate whether SerpinBl regulates NETosis. We found that serpinbl -deficient bone marrow and lung neutrophils are hypersusceptible to NETosis induced by multiple mediators in both an NADPH-dependent and -independent manner, indicating a deeply rooted regulatory role in NETosis. This role is further supported by increased nuclear expansion (representing chromatin decondensation) of PMA-treated serpi'nW-deficient neutrophils compared with wild-type, by migration of SerpinBl from the cytoplasm to the nucleus of human neutrophils that is coincident with or preceding early conversion of lobulated (segmented) nuclei to delobulated (spherical) morphology, as well as by the finding that exogenous human recombinant SerpinBl abrogates NET production. NETosis of serpinbl-deficient neutrophils is also increased in vivo during Pseudomonas aeruginosa lung infection. The findings identify a previously unrecognized regulatory mechanism involving SerpinBl that restricts the production of NETs. [ABSTRACT FROM AUTHOR]