Collagen degradation and neutrophilic infiltration: a vicious circle in inflammatory bowel disease

Abstract

ObjectiveProline–glycine–proline (PGP) has been shown to have chemotactic effects on neutrophils via CXCR2 in several lung diseases. PGP is derived from collagen by the combined action of matrix metalloproteinase (MMP) 8 and/or MMP9 and prolyl endopeptidase (PE). We investigated the role of PGP in inflammatory bowel disease (IBD).DesignIn intestinal tissue from patients with IBD and mice with dextran sodium sulfate (DSS)-induced colitis, MMP8, MMP9 and PE were evaluated by ELISA, immunoblot and immunohistochemistry. Peripheral blood polymorphonuclear cell (PMN) supernatants were also analysed accordingly and incubated with collagen to assess PGP generation ex vivo. PGP levels were measured by mass spectrometry, and PGP neutralisation was achieved with a PGP antagonist and PGP antibodies.ResultsIn the intestine of patients with IBD, MMP8 and MMP9 levels were elevated, while PE was expressed at similar levels to control tissue. PGP levels were increased in intestinal tissue of patients with IBD. Similar results were obtained in intestine from DSS-treated mice. PMN supernatants from patients with IBD were far more capable of generating PGP from collagen ex vivo than healthy controls. Furthermore, PGP neutralisation during DSS-induced colitis led to a significant reduction in neutrophil infiltration in the intestine.ConclusionsThe proteolytic cascade that generates PGP from collagen, as well as the tripeptide itself, is present in the intestine of patients with IBD and mice with DSS-induced colitis. PGP neutralisation in DSS-treated mice showed the importance of PGP-guided neutrophilic infiltration in the intestine and indicates a vicious circle in neutrophilic inflammation in IBD.

Fragments of Citrullinated and MMP-degraded Vimentin and MMP-degraded Type III Collagen Are Novel Serological Biomarkers to Differentiate Crohn’s Disease from Ulcerative Colitis

“…8,9 In IBD, the extracellular matrix [ECM] of the intestine is highly affected by chronic inflammation that leads to imbalanced tissue remodelling 10 which is a result of increased expression of both degenerative proteases, such as matrix metalloproteinases [MMPs] and ECM protein. 11,12 In IBD, several MMPs have been reported to be upregulated during inflammation, including MMP-2, 13,19 8,14,15,16 and 9. 13,14,15 The altered tissue remodelling, led by the MMPs, results in the release of small protein fragments into the surrounding tissue, where these ECM cleavage products may act as chemokines, which in turn can contribute to increased inflammation by increased infiltration by leukocytes, including neutrophils.…”

“…13,14,15 The altered tissue remodelling, led by the MMPs, results in the release of small protein fragments into the surrounding tissue, where these ECM cleavage products may act as chemokines, which in turn can contribute to increased inflammation by increased infiltration by leukocytes, including neutrophils. 16 These protein fragments, also referred to as neoepitopes, 17 can also be released into the circulation, and may be used as biomarkers for diagnostic, disease monitoring, and prognostic purposes. 18 The main collagens found in the ECM of intestinal wall are collagen types I, III, and IV.…”

Glyphosate pathways to modern diseases VI: Prions, amyloidoses and autoimmune neurological diseases

“…The enzyme is expressed predominantly by pathogenic bacteria in the gut, in particular Serratia marcescens, a common pathogen in the gut as well as in the urinary tract; it is often multiply antibiotic-resistant and is a serious threat in hospital-acquired infection [34]. This enzyme is especially important to the pathogens for degrading collagen, providing amino acids as fuel.…”

“…It is conceivable that the pathogens are able to degrade glyphosatecontaminated peptides terminating in proline whereas the human form of the enzyme is not. It is intriguing that the S. marcescens version of prolyl aminopeptidase is unusual in having extra space at the active site [34], which could potentially accommodate the larger glyphosate molecule adjacent to the terminal proline residue. This might also contribute to glyphosate's observed effect on the gut microbiome: excessive growth of pathogens.…”

“…Incomplete collagen degradation by matrix metalloproteinases in the gut could lead to the accumulation of short pro-gly-pro peptides that are resistant to proteolysis. These could then induce the infiltration of neutrophils or the activation of resident immune cells to induce an inflammatory response [34].…”