Ac2-26-Nanoparticles Induce Resolution of Intestinal Inflammation and Anastomotic Healing via Inhibition of NF-κB Signaling in a Model of Perioperative Colitis

Stefan Reischl, Jong Hyun Lee, Joseph Raphael Elias Miltschitzky, Vincent Vieregge, Robert Leon Walter, Vanessa Twardy, Atsuko Kasajima, Helmut Friess, Nazila Kamaly, Philipp Alexander Neumann

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

Background: Although in most patients with inflammatory bowel diseases, conservative therapy is successful, a significant proportion of patients still require surgery once in their lifetime. Development of a safe perioperative treatment to dampen colitis activity without disturbance of anastomotic healing is an urgent and unmet medical need. Annexin A1 (ANXA1) has been shown to be effective in reducing colitis activity. Herein, a nanoparticle-based perioperative treatment approach was used for analysis of the effects of ANXA1 on the resolution of inflammation after surgery for colitis. Methods: Anxa1-knockout mice were used to delineate the effects of ANXA1 on anastomotic healing. A murine model of preoperative dextran sodium sulfate colitis was performed. Collagen-IV-targeted polymeric nanoparticles, loaded with the ANXA1 biomimetic peptide Ac2-26 (Ac2-26-NPs), were synthesized and administered perioperatively during colitis induction. The effects of the Ac2-26-NPs on postoperative recovery and anastomotic healing were evaluated using the disease activity index, histological healing scores, and weight monitoring. Ultimately, whole-genome RNA sequencing of the anastomotic tissue was performed to unravel underlying molecular mechanisms. Results: Anxa1-knockout exacerbated the inflammatory response in the healing anastomosis. Treatment with Ac2-26-NPs improved preoperative colitis activity (P <0.045), postoperative healing scores (P<0.018), and weight recovery (P<0.015). Whole-genome RNA sequencing revealed that the suppression of proinflammatory cytokine and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling was associated with the treatment effects and a phenotypic switch toward anti-inflammatory M2 macrophages. Conclusions: Proresolving therapy with Ac2-26-NPs promises to be a potent perioperative therapy because it improves colitis activity and even intestinal anastomotic healing by the suppression of proinflammatory signaling.

Original languageEnglish
Pages (from-to)1379-1393
Number of pages15
JournalInflammatory Bowel Diseases
Volume27
Issue number9
DOIs
StatePublished - 1 Sep 2021
Externally publishedYes

Keywords

  • annexin A1
  • intestinal anastomotic healing
  • intestinal surgery
  • nanomedicine
  • resolution of inflammation

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