Neutrophils and Activated Macrophages Control Mucosal Immunity by Proteolytic Cleavage of Antileukoproteinase

Abstract

Antileukoproteinase or secretory leukocyte peptidase inhibitor is a small protein which protects the mucosal linings against excessive proteolysis, inflammation, and microbial infection. We discovered that gelatinase B or matrix metalloproteinase (MMP)-9, a secreted zinc-dependent endopeptidase typically found at sites of inflammation, destroys antileukoproteinase by cleavages within both of its two functional domains: the anti-microbial N-terminal and the anti-proteolytic C-terminal domains. Cleaved antileukoproteinase possessed a significantly lower ability to bind lipopolysaccharides (LPS) and a reduced capacity to inhibit neutrophil elastase (NE) activity. Whereas intact antileukoproteinase repressed proinflammatory transcript [prostaglandin-endoperoxide synthase 2 (PTGS2) and IL6] synthesis and protein secretion [e.g., of MMP-9] in human CD14+ blood monocytes stimulated with LPS, this effect was reduced or lost for cleaved antileukoproteinase. We demonstrated the in vivo presence of antileukoproteinase cleavage fragments in lower airway secretions of non-cystic fibrosis bronchiectasis patients with considerable levels of neutrophils and, hence, elastase and MMP-9 activity. As a comparison, other MMPs (MMP-2, MMP-7, and MMP-8) and serine proteases (NE, cathepsin G, and proteinase 3) were also able to cleave antileukoproteinase with similar or reduced efficiency. In conclusion, in specific mucosal pathologies, such as bronchiectasis, neutrophils, and macrophage subsets control local immune reactions by proteolytic regulation, here described as the balance between MMPs (in particular MMP-9), serine proteases and local tissue inhibitors.

Tear Film Proteome of Healthy Domestic Cats

“…is is corroborated in the interaction network since homologs of this protein have strong interaction with proteins such as myeloperoxidase (score 0.755), which is microbicidal [53] and antileukoproteinase (score 0.969), a proteinase inhibitor that modulates the immune response after a bacterial infection [54]. is explains the fact that we found lactotransferrin with high abundance in cats' TF since the samples were from healthy animals.…”

TAILS proteomics reveals dynamic changes in airway proteolysis controlling protease activity and innate immunity during COPD exacerbations

“…Importantly, we were able to demonstrate that processing of SLPI was directly related to increasing elastase activity. A number of studies have demonstrated protease inhibitor cleavage events in vitro that may be responsible for our findings; for example, SLPI is cleaved by cathepsins B, L, and S in COPD and by MMP9 and neutrophil elastase in cystic fibrosis (39,41,42). We (40) too have previously shown that MMP14 cleaves and inactivates SLPI.…”

Atypical response to bacterial coinfection and persistent neutrophilic bronchoalveolar inflammation distinguish critical COVID-19 from influenza

“…The abundantly present protease inhibitors in the COVID-19 patient lungs could also be inactivated by proteolytic cleavage and still remain detectable by ELISA. For the protease inhibitor SLPI, it has been shown that MMP-9 and other neutrophil-derived proteases can cleave SLPI, resulting in a reduced capacity to inhibit neutrophil elastase activity ( 49 ).…”