Chitinase 3-like-1 exacerbates intestinal inflammation by enhancing bacterial adhesion and invasion in colonic epithelial cells.
OBJECTIVE
Dysregulated host/microbial interactions appear to play a central role in the development of inflammatory bowel disease (IBD). However, molecular events leading to the dysregulation have not yet been defined fully. Studies were designed to characterize a key molecule that is involved in the dysregulation.


METHODS
Colonic mucosal RNA from C57BL/6 mice on days 4 and 8 with administration of 4% dextran sulfate sodium for 5 days were subjected to DNA microarray analysis. Chitinase 3-like-1 (CHI3L1) messenger RNA and protein expressions were examined by reverse-transcription polymerase chain reaction and immunohistochemistry. A gentamicin protection assay of Salmonella typhimurium was performed using epithelial cell lines that are engineered genetically to overexpress or lack mouse CHI3L1. To examine the functional role of CHI3L1 in vivo, anti-CHI3L1 antibody was administered into the dextran sulfate sodium colitis model.


RESULTS
Microarray analysis identified that CHI3L1 is up-regulated specifically in inflamed mucosa. The expression of CHI3L1 protein clearly was detectable in lamina propria and colonic epithelial cells (CECs) in several murine colitis models and ulcerative colitis and Crohn's disease patients but absent in normal controls. The gentamicin protection assays using intracellular bacteria showed that CHI3L1 is required for the enhancement of adhesion and internalization of these bacteria in CEC. In vivo neutralization experiments showed that CHI3L1 contributes to the facilitation of bacterial invasion into the intestinal mucosa and the development of acute colitis.


CONCLUSIONS
CHI3L1 plays a pathogenic role in colitis, presumably by enhancing the adhesion and invasion of bacteria on/into CEC. Inhibition of CHI3L1 activity would be a novel therapeutic approach for IBD.
Mizoguchi
Emiko
E
Center for the Study of Inflammatory Bowel Disease, Gastroenterology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, 02114, USA.
D000818:Animals; D001422:Bacterial Adhesion / Q000502:physiology*; D003093:Colitis, Ulcerative / Q000235:genetics / Q000473:pathology; D003106:Colon / Q000382:microbiology / Q000473:pathology*; D017931:DNA Primers; D004195:Disease Models, Animal; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000502:physiology; D005260:Female; D006801:Humans; D016753:Interleukin-10 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D007413:Intestinal Mucosa / Q000382:microbiology / Q000473:pathology*; D037102:Lectins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D034741:RNA, Small Interfering / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000172:deficiency / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012486:Salmonella typhimurium / Q000472:pathogenicity; D001619:beta-N-Acetylhexosaminidases / Q000502:physiology*
D017931:DNA Primers; D016326:Extracellular Matrix Proteins; D037102:Lectins; D034741:RNA, Small Interfering; D011948:Receptors, Antigen, T-Cell; D016753:Interleukin-10; C429541:Chil3 protein, mouse; D001619:beta-N-Acetylhexosaminidases