Collagen-binding integrin alpha1beta1 regulates intestinal inflammation in experimental colitis.
Central to inflammatory responses are the integrin-mediated adhesive interactions of cells with their ECM-rich environment. We investigated the role of the collagen-binding integrin alpha(1)beta(1) in intestinal inflammation using the mouse model of colitis induced by dextran sodium sulfate (DSS). mAb's directed against murine alpha(1) were found to significantly attenuate inflammation and injury in DSS-treated wild-type mice; similar protection was seen in mice deficient for alpha(1)beta(1) integrin. Blockade or loss of alpha(1)beta(1) was also associated with decreased mucosal inflammatory cell infiltrate and cytokine production. Importantly, we demonstrated that development and alpha(1)-mediated inhibition of DSS-induced colitis occurred independently of lymphocytes (Rag-2(-/-) mice), and identified the monocyte as a key alpha(1)beta(1)-expressing cell type involved in the development of colitis in this model. In response to DSS, both alpha(1) deficiency and anti-alpha(1) mAb treatment significantly reduced monocyte accumulation and activation within the lamina propria. In summary, the data demonstrate that engagement of leukocyte-associated alpha(1)beta(1) receptors with ECM plays a pivotal role in mediating intestinal inflammation via promotion of monocyte movement and/or activation within the inflamed interstitium. Therapeutic strategies designed to disrupt such interactions may prove beneficial in treating intestinal inflammation.
Krieglstein
Christian F
CF
Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71130-3932, USA.
Cerwinka
Wolfgang H
WH
Sprague
Andrew G
AG
Laroux
F Stephen
FS
Grisham
Matthew B
MB
Koteliansky
Victor E
VE
Senninger
Norbert
N
Granger
D Neil
DN
de Fougerolles
Antonin R
AR
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D039481:CD11b Antigen / Q000378:metabolism; D003092:Colitis / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D003094:Collagen / Q000378:metabolism*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics; D016264:Dextran Sulfate / Q000008:administration & dosage / Q000633:toxicity; D004195:Disease Models, Animal; D006801:Humans; D007150:Immunohistochemistry; D007202:Indicators and Reagents / Q000633:toxicity; D039222:Integrin alpha1beta1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000276:immunology / Q000473:pathology*; D008214:Lymphocytes / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009000:Monocytes / Q000378:metabolism; D009687:Nuclear Proteins; D009195:Peroxidase / Q000378:metabolism; D011485:Protein Binding
D000911:Antibodies, Monoclonal; D039481:CD11b Antigen; D016207:Cytokines; D004268:DNA-Binding Proteins; D007202:Indicators and Reagents; D039222:Integrin alpha1beta1; D009687:Nuclear Proteins; C499311:RAG2 protein, human; C499308:Rag2 protein, mouse; C064655:V(D)J recombination activating protein 2; D003094:Collagen; D016264:Dextran Sulfate; D009195:Peroxidase