Immunomodulatory peptides attenuate local and systemic inflammation in a murine DSS-colitis model
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Notice bibliographique
Résumé
Innate defence regulator (IDR) peptides are synthetic derivatives of endogenous host defence peptides (HDPs), under investigation as novel anti-infective agents. IDRs lack effective antimicrobial activity; rather, they enhance bacterial clearance by increasing leukocyte recruitment to infection sites while simultaneously suppressing harmful inflammation. We hypothesized that IDRs might be efficacious in attenuating inflammation in a murine DSS colitis model, given that dysfunctional innate immune responses to gut microflora are believed to drive the etiopathogenesis of IBD. Two peptides, IDR-1002 and IDR-1018, were selected for their ability to modulate PBMC cytokine production in vitro, and enhance clearance of Staphylococcus aureus and Escherichia coli in murine infection models. Using a standard model of DSS-colitis, colonic inflammation was induced by addition of 2.75% DSS (w/v) to the drinking water (day 0) of 6-week old male C57BL/6 mice. Mice were randomized to receive 2 doses of IDR-1002 or IDR-1018, 3 doses of IDR-1018, or 3 doses of the endogenous human HDP LL-37. Peptides (200 ug) were administered intraperitoneally on day 1, 3, and 6 (3-dose regime), or on day 4 and 7 (2-dose regime), and mice were euthanized on day 9. Weights were recorded daily, and serum was collected on day 1, 7, and 9, for ELISA quantification of Serum Amyloid A. Colons were excised from cecum to rectum and homogenized for quantification of IL-12p70, IL-10, TNF-a, IL-6, and IFN-g. Colonic myeloperoxidase (MPO) was quantified as a measure of neutrophil infiltration. Sections of the cecum and proximal, mid, and distal colons were formalin fixed, and used to prepare H&E slides for histopathological scoring. Mice administered DSS showed progressive weight loss beginning on day 4 or 5. Both IDR-1002 and IDR-1018 slowed the weight loss trajectory as revealed by linear regression analysis. Relative to healthy controls, colitic animals showed a 4-fold reduction in tissue IL-10, however treatment with IDR-1018 restored IL-10 to healthy levels. Serum amyloid A, a systemic correlate of inflammation, was reduced by 3-4 fold in IDR-1002 and IDR-1018 treated mice. In contrast, tissue levels of MPO, a marker of PMN infiltration, was increased by both IDR-1002 and IDR-1018. Of the HDPs tested, only IDR-1018 improved the histological appearance of colitis, predominately in the cecum and distal colon. When taken together, these data provide the first evidence that IDR peptides being developed as anti-infective agents might one day be used in the treatment of auto-inflammatory diseases. Further research is needed to determine if the effects of IDRs in DSS-colitis are due to enhanced immune killing of intestinal microbiota, attenuation of the inflammatory process, or both.
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Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découle