C-type lectin SIGN-R1 has a role in experimental colitis and responsiveness to lipopolysaccharide.
Pathogen recognition receptors (PRRs) function to maintain the balance between controlled responses to pathogens and uncontrolled innate immune activation leading to inflammation. In the context of commensal bacteria and the etiology of inflammatory bowel disease, although a role for the TLRs is known, there is a less defined function for C-type lectin receptors (CLRs). We demonstrate that mice deficient ((-/-)) in the CLR specific intracellular adhesion molecule-3 grabbing nonintegrin homolog-related 1 (SIGN-R1) (CD209b) have reduced susceptibility to experimental colitis, with a reduction in the disease severity, colon damage, and levels of the proinflammatory cytokines IL-1beta, TNF-alpha, and IL-6. To determine whether SIGN-R1(-/-) mice had a systemic defect in innate activation, we examined the responsiveness of macrophages from SIGN-R1(-/-) mice to TLR ligands. SIGN-R1(-/-) peritoneal macrophages, but not bone marrow-derived macrophages, have a specific defect in IL-1beta and IL-18 production, but not other cytokines, in response to the TLR4 ligand LPS. In vivo SIGN-R1(-/-) mice had significantly reduced susceptibility to LPS-induced shock. To address the synergistic relationship between SIGN-R1 and TLR4 in the context of experimental colitis, SIGN-R1/TLR4(-/-) mice were generated. SIGN-R1/TLR4(-/-) mice displayed reduced susceptibility to experimental colitis relative to severity of disease observed in wild-type or TLR4(-/-) mice. The in vivo use of a blocking mAb confirmed a functional role for SIGN-R1 in LPS-induced shock and experimental colitis. These data indicate a role for SIGN-R1 in the regulation of inflammation in a model of experimental colitis and illustrate that SIGN-R1 is a critical innate factor in response to LPS.
Institute of Molecular Medicine, St. James's Hospital, Trinity College Dublin, Dublin, Ireland.
Sean P
SP
Saunders
Jillian L
JL
Barlow
Caitriona M
CM
Walsh
Agustin
A
Bellsoi
Philip
P
Smith
Andrew N J
AN
McKenzie
Padraic G
PG
Fallon
D000818:Animals; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D003092:Colitis / Q000139:chemically induced / Q000235:genetics / Q000503:physiopathology*; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016264:Dextran Sulfate; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D020022:Genetic Predisposition to Disease; D020382:Interleukin-18 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D037181:Lectins, C-Type / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008070:Lipopolysaccharides / Q000633:toxicity*; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D012769:Shock / Q000139:chemically induced / Q000235:genetics / Q000503:physiopathology; D051195:Toll-Like Receptor 2 / Q000172:deficiency / Q000235:genetics; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
D015815:Cell Adhesion Molecules; D016264:Dextran Sulfate; D020382:Interleukin-18; D053583:Interleukin-1beta; D015850:Interleukin-6; D037181:Lectins, C-Type; D008070:Lipopolysaccharides; D053594:Myeloid Differentiation Factor 88; D011956:Receptors, Cell Surface; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C507780:Myd88 protein, mouse; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse