Impaired immunity to intestinal bacterial infection in stromelysin-1 (matrix metalloproteinase-3)-deficient mice.
Infection of mice with the intestinal bacterial pathogen Citrobacter rodentium results in colonic mucosal hyperplasia and a local Th1 inflammatory response similar to that seen in mouse models of inflammatory bowel disease. Matrix metalloproteinases (MMPs) have been shown to mediate matrix remodeling and cell migration during tissue injury and repair in the intestine. We have previously shown enhanced pathology in infected TNFRp55-/-, IL-12p40-/-, and IFN-gamma-/- mice, and here we show that this is associated with an increase in stromelysin-1 (MMP3) transcripts in colonic tissues. We have therefore investigated the role of MMP3 in colonic mucosal hyperplasia and the local Th1 responses using MMP3-/- mice. In MMP3-/- mice, similar mucosal thickening was observed after infection as in wild-type (WT) mice. Colonic tissues from MMP3-/- mice showed a compensatory increase in the expression of other MMP transcripts, such as MMP7 and MMP12. However, MMP3-/- mice showed delayed clearance of bacteria and delayed appearance of CD4+ T lymphocytes into intestinal lamina propria. CSFE-labeled mesenteric lymph node CD4+ T lymphocytes from infected WT mice migrated in fewer numbers into the mesenteric lymph nodes and colon of MMP3-/- mice than into those of WT mice. These studies show that mucosal remodeling can occur in the absence of MMP3, but that MMP3 plays a role in the migration of CD4+ T lymphocytes to the intestinal mucosa.
Division of Infection, Inflammation and Repair, University of Southampton School of Medicine, UK.
Chris K F
CK
Li
Sylvia L F
SL
Pender
Karen M
KM
Pickard
Victoria
V
Chance
Judith A
JA
Holloway
Alan
A
Huett
Nathalie S
NS
Gonçalves
John S
JS
Mudgett
Gordon
G
Dougan
Gad
G
Frankel
Thomas T
TT
MacDonald
D000818:Animals; D015703:Antigens, CD / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology; D002465:Cell Movement; D044082:Citrobacter rodentium; D003106:Colon / Q000201:enzymology / Q000473:pathology; D003713:Dendritic Cells / Q000502:physiology; D004756:Enterobacteriaceae Infections / Q000276:immunology* / Q000473:pathology; D005260:Female; D007371:Interferon-gamma / Q000502:physiology; D018664:Interleukin-12 / Q000502:physiology; D053762:Interleukin-12 Subunit p40; D007410:Intestinal Diseases / Q000276:immunology* / Q000473:pathology; D019278:Matrix Metalloproteinase 3 / Q000172:deficiency / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D021122:Protein Subunits / Q000502:physiology; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology; D047888:Receptors, Tumor Necrosis Factor, Type I
D015703:Antigens, CD; D053762:Interleukin-12 Subunit p40; D021122:Protein Subunits; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D018664:Interleukin-12; D007371:Interferon-gamma; D019278:Matrix Metalloproteinase 3