Genetic deficiency in the chemokine receptor CCR1 protects against acute Clostridium difficile toxin A enteritis in mice.
OBJECTIVE
The role of the CC chemokine receptor (CCR) 1 in acute enteritis was investigated by subjecting CCR1 knockout mice to Clostridium difficile toxin A treatment.


METHODS
Toxin A or vehicle was injected into ileal loops in anesthetized wild-type, CCR1-/- and macrophage inhibitory protein (MIP)-1alpha-/- mice. After 1-4 hours, fluid accumulation was calculated, and the loops were processed for histology, myeloperoxidase activity, regulated on activation, normal T cell expressed and secreted (RANTES) production, and messenger RNA measurements.


RESULTS
Toxin A induced in all mice a significant (P < 0.05) increase in ileal fluid accumulation, epithelial damage, and neutrophil infiltration, with all parameters being significantly (P < 0.01) lower in CCR1-/- and MIP-1alpha-/- mice. Ileal messenger RNA expression of the CCR1 ligands MIP-1alpha and RANTES and RANTES synthesis were increased in toxin A-treated wild-type mice. The RANTES antagonist Met-RANTES significantly (P < 0.01) reduced the toxin A-induced increases in ileal fluid accumulation and myeloperoxidase activity in wild-type mice.


CONCLUSIONS
C. difficile toxin A-induced murine enteritis involves CCR1 and its ligands MIP-1alpha and RANTES, which may be important mediators of the neutrophil recruitment characterizing acute, enterotoxin-mediated enteritis.
Morteau
Olivier
O
Division of Pulmonary Medicine, Perlmutter Laboratory, Children's Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA.
Castagliuolo
Ignazio
I
Mykoniatis
Andreas
A
Zacks
Jeff
J
Wlk
Michael
M
Lu
Bao
B
Pothoulakis
Charalabos
C
Gerard
Norma P
NP
Gerard
Craig
C
D000208:Acute Disease; D000818:Animals; D001427:Bacterial Toxins / Q000633:toxicity*; D001826:Body Fluids / Q000378:metabolism; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5 / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology; D002772:Cholera Toxin / Q000633:toxicity; D004760:Enterocolitis / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D004768:Enterotoxins / Q000633:toxicity*; D015870:Gene Expression / Q000276:immunology; D007082:Ileum / Q000378:metabolism / Q000473:pathology; D019402:Macrophage Inflammatory Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000032:analysis; D054389:Receptors, CCR1; D019707:Receptors, Chemokine / Q000235:genetics*
D001427:Bacterial Toxins; C515301:Ccr1 protein, mouse; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D004768:Enterotoxins; D019402:Macrophage Inflammatory Proteins; C108335:RANTES, Met-; D012333:RNA, Messenger; D054389:Receptors, CCR1; D019707:Receptors, Chemokine; C041348:tcdA protein, Clostridium difficile; D002772:Cholera Toxin