P073. ADAMDEC1: A novel molecule in inflammation and bowel disease
N. O'Shea1, G. Sewell1, T. Chew1, S. Bloom2, A. Smith2, A. Segal2
1University College London, Division of Medicine, London, United Kingdom; 2University College London Hospital, Gastroenterology, London, United Kingdom
Background: Innate immunity is attenuated in patients with Crohn's disease (CD), with impaired neutrophil recruitment to skin and bowel, delayed clearance of E. coli from skin, and impaired secretion of pro-inflammatory cytokines from macrophages [1,2]. This primary defect of acute inflammation results in failure to eradicate bacterial flora entering tissues leading to the characteristic chronic granulomatous inflammation. Microarray analysis of monocyte derived macrophage mRNA expression, confirmed by qPCR, revealed that ADAMDEC1 (ADAM like Decysin 1), part of a family of proteins involved in wound healing and tissue repair, was under-expressed in 6 of 60 CD patients. To determine the role of this protein (expressed almost exclusively in macrophages, dendritic cells and in the gastrointestinal tract) we examined E. coli induced inflammation, and DSS colitis in Adamdec1 knockout (KO) mice.
Methods: Mice were exposed to 2% DSS for 7 days (wild type (WT) litter mate controls were age, weight and sex matched, n = 11 per group). Clinical colitis scores (weight loss, PR blood, loose stool) were recorded daily. Histology was obtained from small and large bowels.
For bacterial inflammation, 5×108 heat killed E. coli (HkEc) were injected subcutaneously into the backs of KO and WT mice (n = 8 per group). Mice were weighed, injection sites inspected for ulceration and subcutaneous nodules measured, daily. Injection sites were excised at different times for histology and identification of infiltrating cells by FACS.
Results: Adamdec1 KO mice were more susceptible to DSS colitis. They demonstrated higher clinical colitis scores with earlier and more dramatic weight loss (p < 0.001) and a more florid inflammatory response on histology.
In response to subcutaneous E. coli, Adamdec1 KO mice had smaller inflammatory nodules and less ulceration after 4872 hours, than WT mice (p < 0.001).
Conclusions: Mice lacking Adamdec1 develop a phenotype that closely mirrors that observed in patients with CD; an attenuated E. coli induced acute inflammatory response and abnormally severe bowel inflammation after DSS. These results suggest ADAMDEC1 plays an important role in the acute inflammatory response to bacteria and has a protective role within the intestine; reduced levels may have a pivotal role in the development and persistence of CD.
1. Marks DJ et al (2006), Defective acute inflammation in Crohn's disease, Lancet, 66878, 367(9511).
2. Smith AM et al (2009), Disordered macrophage cytokine secretion underlies impaired acute inflammation and bacterial clearance in Crohn's disease, Journal of Experimental Medicine, 188397, 206(9).