Neutrophils are short-lived leukocytes with vital functions in host defense. Neutrophils are massively recruited to extravascular sites in response to danger signals. This immediate, life saving, inflammatory response can turn against the host if its intensity and duration are dysregulated leading to tissue injury and/or failed immune response to pathogens. The dual protective/pathologic role of neutrophils is reflected by the functions of neutrophil serine proteases, potent granule enzymes that hydrolyze other proteins. Neutrophil serine proteases (or NSPs) directly kill pathogens after fusion of the NSP-rich granules with the microbe-containing phagosome. However, when released extracellularly and in excess of the anti-protease shield, NSPs are harmful by fueling the inflammatory response and by destroying extracellular matrix proteins and immune defense proteins. The aim of the proposed work is to investigate the regulation of NSPs by the serpin (SERine Protease INhibitors) family of proteins in health and disease. Specifically, we will study the role of serpinB1, one of the best inhibitors of the three NSPs: neutrophil elastase, cathepsin G and proteinase-3. We have previously shown that (i) serpinB1, a cytoplasmic inhibitor of NSPs carried at high levels in neutrophils, provides a physiological and vital shield against pathologic actions of NSPs during lung infection, and (ii) serpinB1 prevents the early death of neutrophils during infection. Our preliminary data now indicates that serpinB1 is required to preserve the size of the neutrophil reservoir in bone marrow and protects lung epithelial cells against NSPs. The proposed work will elucidate the protective functions of serpinB1 in myeloid cells and lung epithelial cells. Overall, these studies will provide highly significant advances in understanding pathologic mechanisms due to excess NSPs in bone marrow homeostasis and pulmonary disease.
Field of science
- /medical and health sciences/basic medicine/physiology/homeostasis
- /medical and health sciences/health sciences/public and environmental health/epidemics prevention/immunisation
- /natural sciences/biological sciences/biochemistry/biomolecules/proteins
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