Protease inhibitory activity of secretory leukocyte protease inhibitor ameliorates murine experimental colitis by protecting the intestinal epithelial barrier

Abstract

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder in the intestine, and the dysfunction of intestinal epithelial barrier (IEB) may trigger the onset of IBD. Secretory leukocyte protease inhibitor (SLPI) is a serine protease inhibitor that has been implicated in the tissue‐protective effect in the skin and lung. We found that SLPI was induced in lipopolysaccharides‐treated colon carcinoma cell line and in the colon of dextran sulfate sodium (DSS)‐treated mice. SLPI‐deficient mice were administered DSS to induce colitis and sustained severe inflammation compared with wild‐type mice. The colonic mucosa of SLPI‐deficient mice showed more severe inflammation with neutrophil infiltration and higher levels of proinflammatory cytokines compared with control mice. Moreover, neutrophil elastase (NE) activity in SLPI‐deficient mice was increased and IEB function was severely impaired in the colon, accompanied with the increased number of apoptotic cells. Importantly, we demonstrated that DSS‐induced colitis was ameliorated by administration of protease inhibitor SSR69071 and recombinant SLPI. These results suggest that the protease inhibitory activity of SLPI protects from colitis by preventing IEB dysfunction caused by excessive NE activity, which provides insight into the novel function of SLPI in the regulation of gut homeostasis and therapeutic approaches for IBD.

The phenotype of the gut region is more stably retained than developmental stage in piglet intestinal organoids

“…Only one of the DEG identified in vivo ( SLPI , coding for a protease inhibitor regulating the epithelial barrier) ( Ozaka et al, 2021 ) was also differentially expressed at each passage between jejunum organoids from suckling and weaned piglets and in the same direction as observed in vivo ( Figures 6B–D and Supplementary Table S8 ). Some DEG identified between jejunum crypts of suckling and weaned piglets ( PI3, ST14, PIGR, GPX2, CGN, BAX, LBP, CLDN3, SMOC2, REG4, CFTR ) were differentially expressed between jejunum organoids from suckling and weaned piglets at one (P0 or P2) but not at all passages and not always in the same direction.…”

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

“…Benefits of SLPI administration or overexpression have previously been suggested for various chronic inflammation models including asthma [ 48 ], emphysema [ 31 ], and arthritis [ 49 ] and more recently, colitis [ 50 ]. A clinical trial involving the administration of aerosolised hrSLPI to cystic fibrosis patients decreased IL-8 levels and elastase activity in BAL fluid, highlighting its potential in the treatment of human chronic lung disease [ 29 ].…”

Secretory Leukocyte Protease Inhibitor Protects Against Severe Urinary Tract Infection in Mice

“…This is potentially important because Slpi -/- mice had histologically more severe and prolonged inflammation in our experiments, which could be explained by an overabundance of NE found in the bladder lumen. Together, these findings imply that SLPI, similar to the serpin antiprotease family (24), helps to resolve inflammation in the bladder following infection by limiting the mucosal damaging protease activity of NE (64) in the urinary tract.…”

“…SLPI is known to have immunomodulatory properties, including the ability to regulate production of NFkB-derived inflammatory cytokines (49,51,62) and modulate neutrophil function (63,64). Our observation that Slpi -/- mice demonstrate evidence of immune dysregulation at multiple stages of UPEC cystitis support an immune regulatory role for SLPI in the urinary tract.…”