Intercellular adhesion molecule-1 (ICAM-1) deficiency protects mice against severe forms of experimentally induced colitis

Abstract

ICAM-1 (CD54), the ligand for LFA-1 and Mac-1, is up-regulated during inflammatory reaction on the activated vascular endothelium. To determine its role in intestinal inflammation, we induced acute experimental colitis in mice with a deleted ICAM-1 gene, by feeding them with 3% dextran sodium sulphate (DSS) in drinking water for 7 days. Chronic colitis was elicited by DSS similarly, followed by 2 weeks with water. In the acute phase of inflammation, ICAM-1-deficient mice exhibited a significantly lower mortality rate (5%) than control C57Bl/6J mice (35%). Control animals, but not the ICAM-1-deficient mice, exhibited diarrhoea and rectal bleeding. Histological examination of large-bowel samples evaluated the intensity of inflammatory changes, and type and extent of mucosal lesions. In the acute phase, 33.3% of samples from ICAM-1-deficient mice exhibited mucosal defects (flat and fissural ulcers), predominantly mild to moderate inflammatory infiltrate within the lamina propria mucosae and lower grades of mucosal lesions. Much stronger inflammatory changes were present in control animals, flat ulcers (sometimes multiple) and fissural ulcers being observed in 62.5% of samples. Mucosal inflammatory infiltrate was moderate to severe, typically with higher grades of mucosal lesions. In chronic colitis, smaller inflammatory changes were found in the large bowel. The two mouse strains differed, the chronic colitis being accompanied by an increased serum level of anti-epithelial IgA autoantibodies in C57Bl/6 control mice but not in ICAM-1-deficient mice. These findings provide direct evidence of the participation of ICAM-1 molecule in the development of experimentally induced intestinal inflammation.

Fig. 1

Histopathological manifestations of acute colitis. C57Bl/6 control mice: (A) flat ulcer and hypersecretion of mucin in adjacent colonic mucosa; (B) narrow fissural ulcer. ICAM-1-deficient mice: (C) flat ulcer; (D) grade 3 lesion with cystic dilatation of the crypt and goblet cell reduction. (Haematoxylin and eosin, mag. × 63.)

Fig. 2

Histopathological manifestations of chronic phase of colitis. C57Bl/6 control mice: (A) large grade 3 lesion, probably re-epithelized flat ulcer; (B) grade 2 lesion. ICAM-1-deficient mice: (C) grade 1–3 lesion. (D) Goblet cell reduction and proliferation of crypt epithelium are present in the vicinity of the lesion. (Haematoxylin and eosin, mag. × 63.)

Fig. 3

Presence of anti-epithelial antibodies determined by ELISA in sera of ICAM-1-deficient and control mice with chronic colitis (seven mice were used per group). Results are expressed as a percentage of the reactivity of reference serum. Values are indicated as the mean ± s.e.m. of each group. Statistically significant differences were found in the levels of IgA antibodies (at P ≤ 0.001) between dextran sodium sulphate (DSS)-treated ICAM-1-deficient and wild-type control mice and between DSS-induced and untreated mice. ▪, DSS; □, water.