Mucosal Inflammation

Gastrointestinal Inflammation

The mucosa of the gastrointestinal tract is the first line of defence against pathogens in the lumen of the intestines. The mucosal lining consists of a layer of mucus which covers the one-cell thick epithelial lining of the intestines. The underlying lamina propria consists of cells that display Pathogen Recognition Molecules (PRM) such as Toll-like receptors that are able to engage with Pathogen Associated Molecular Patterns (PAMP’s). This interaction is responsible for initiation of the pro-inflammatory cytokine cascade that drives the inflammatory response. A dysregulation in this defence can shift the outcome for the host from beneficial to highly detrimental.

Inflammatory Bowel Diseases (IBD) are complex autoimmune diseases affecting approximately 1-2 of every 1000 people in developed countries. It is comprised of two phenotypes, Crohn’s Disease and Ulcerative Colitis which develops through inflammation and ulceration of the small intestine and colon, respectively, and progresses with intermittent periods of remission. The onset of this pathological condition, although still unknown, is believed to be due to different genetics and environmental factors that cause a dysregulation of the host immune defence resulting in an immune response against the commensal microflora of the intestines.

Our current strategy is to interrupt this inflammatory cascade by the process of RNA interference (RNAi) using nanoparticles containing pro-inflammatory cytokine-specific small interfering RNA (siRNA).

By Troels Bo Thomsen

 

Treatment for Gastrointestinal Inflammation

Under the pathological conditions of IBD, the commensal microflora (yellow) gains access to the lamina propria where highly conserved microbial motifs interacts with receptors of the innate immune system (blue). This interaction activates transcription and translation and results in the secretion of cytokines such as TNFα (red) which function as a downstream signal for sustained inflammation. Chitosan/siRNA nanoparticles (green) endocytosed by macrophages and dendritic cells, release siRNA cargo in the cytoplasm which results in target specific RNA interference and degradation of the cytokine mRNA, thereby, blocking the downstream signaling affects.

 

 

 

Polymer and nanoparticle interactions with mucus

The physicochemical properties of the nanoparticles have been shown to influence trafficking through mucus but precise determination of surface properties and the effect on the morphology of the mucus have not been investigated. In our work, we aim to study mucoadehesiveness, mucus integrity effects and nanoparticle trafficking to select mucus penetrative materials.

 

A) The mucosal surfaces lining the respiratory, gastrointestinal and genitourinary tracts and eyes. B) The mucosal epithelial border restricts penetration of luminal particulates (right) through a combination of overlying mucus composed of a lower steady layer (dark) and an upper watery layer (light), tight cellular junctions and ciliary clearance. Exploitation of mucoadhesive and mucopermeable particles allows cellular uptake across mucosal surfaces (left). C) Particles diffusing through the network of mucin fibers.

 

 

 

 

Methods for studying interactions between mucus and nanoparticles

A) Schematic representation of the well-in-well setup, with the mucin in the bottom, and the particle solution on top (green). As the particles penetrate through the mucin, they are visualized by confocal microscopy (B) and counted at T=0, 1 and 2 hours (C)

 

 

 

 

Collaborators:

Jørgen Agnholt, Department of Clinical Medicine, Aarhus University Hospital

Jens Kelsen, Department of Clinical Medicine, Aarhus University Hospital

Bent Deleuran, Department of Biomedicine, Aarhus University

Jørgen Kjems, Interdisciplinary Nanoscience Center, iNANO, Aarhus University

George Kollias, Biomedical Sciences Research Center ‘Alexander Fleming’, Athens

Mark Behlke, Integrated DNA Technologies, Inc., USA

Paul McCray, University of Iowa

Katarina Ribbeck, Department of Biological Engineering, Massachusetts Institute of Technology

Recent Publications

Sort by: Date | Author | Title

  1. Martirosyan, A, Olesen, MJ & Howard, KA 2014, 'Chitosan-Based Nanoparticles for Mucosal Delivery of RNAi Therapeutics' Advances in Genetics, bind 88, s. 325-352. DOI: 10.1016/B978-0-12-800148-6.00011-0
  2. Gonzalez, BB, Nielsen, EJB, Thomsen, TB & Howard, K 2013, Mucosal Delivery of RNAi Therapeutics. i KA Howard (red.), RNA Interference from Biology to Therapeutics. Springer, Advances in Delivery Science and Technology, s. 97-125.