Secretory Leucoprotease Inhibitor (SLPI) Promotes Survival during Acute Pseudomonas aeruginosa Infection by Suppression of Inflammation Rather Than Microbial Killing

• Published in: Biomolecules (Basel, Switzerland) Vol. 12; no. 12; p. 1728
• Main Authors: Osbourn, Megan, Rodgers, Aoife M, Dubois, Alice V, Small, Donna M, Humphries, Fiachra, Delagic, Nezira, Moynagh, Paul N, Weldon, Sinéad, Taggart, Clifford C, Ingram, Rebecca J
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 22.11.2022; MDPI
• Subjects: Animals; Anti-inflammatory agents; Bacterial infections; Bone marrow; Bronchus; Chemokines; Cloning; Datasets; Flow cytometry; Histology; Humans; IKK protein; infection; Infections; Inflammation; Inflammation - metabolism; Inflammation - microbiology; Inflammatory diseases; Lavage; Lipopolysaccharides; Lipoteichoic acid; Lungs; Macrophages; Manufacturers; MAP kinase; Mice; Neutrophils; NF-κB protein; Pathogens; Phosphorylation; Proteins; Pseudomonas; Pseudomonas aeruginosa; Pseudomonas Infections - metabolism; Pseudomonas Infections - therapy; Recombinant Proteins - administration & dosage; Respiratory distress syndrome; secretory leucoprotease inhibitor; Secretory Leukocyte Peptidase Inhibitor - administration & dosage; Secretory Leukocyte Peptidase Inhibitor - metabolism; Sepsis; Serum levels; SLPI; Software; United Kingdom > UK; United States > US; infection; secretory leucoprotease inhibitor; SLPI; Pseudomonas; inflammation
• ISSN: 2218-273X; 2218-273X
• DOI: 10.3390/biom12121728

Secretory leucoprotease inhibitor (SLPI) has multifaceted functions, including inhibition of protease activity, antimicrobial functions, and anti-inflammatory properties. In this study, we show that SLPI plays a role in controlling pulmonary infection. Mice lacking SLPI were highly susceptible to infection, however there was no difference in bacterial burden. Utilising a model of LPS-induced lung inflammation, human recombinant SLPI (hrSLPI) administered intraperitoneally suppressed the recruitment of inflammatory cells in the bronchoalveolar lavage fluid (BALF) and resulted in reduced BALF and serum levels of inflammatory cytokines and chemokines. This anti-inflammatory effect of hrSLPI was similarly demonstrated in a systemic inflammation model induced by intraperitoneal injection of LPS from various bacteria or lipoteichoic acid, highlighting the broad anti-inflammatory properties of hrSLPI. Moreover, in bone-marrow-derived macrophages, hrSLPI reduced LPS-induced phosphorylation of p-IkB-α, p-IKK-α/β, p-P38, demonstrating that the anti-inflammatory effect of hrSLPI was due to the inhibition of the NFκB and MAPK pathways. In conclusion, administration of hrSLPI attenuates excessive inflammatory responses and is therefore, a promising strategy to target inflammatory diseases such as acute respiratory distress syndrome or sepsis and could potentially be used to augment antibiotic treatment.