Crucial pathophysiological role of CXCR2 in experimental ulcerative colitis in mice.
Polymorphonuclear leukocyte infiltration and activation into colonic mucosa are believed to play a pivotal role in mediating tissue damage in human ulcerative colitis (UC). Ligands of human CXC chemokine receptor 1 and 2 (CXCR1/R2) are chemoattractants of PMN, and high levels were found in the mucosa of UC patients. To investigate the pathophysiological role played by CXCR2 in experimental UC, we induced chronic experimental colitis in WT and CXCR2(-/-) mice by two consecutive cycles of 4% dextran sulfate sodium administration in drinking water. In wild-type (WT) mice, the chronic relapsing of DSS-induced colitis was characterized by clinical signs and histopathological findings that closely resemble human disease. CXCR2(-/-) mice failed to show PMN infiltration into the mucosa and, consistently with a key role of PMN in mediating tissue damage in UC, showed limited signs of mucosal damage and reduced clinical symptoms. Our data demonstrate that CXCR2 plays a key pathophysiological role in experimental UC, suggesting that CXCR2 activation may represent a relevant pharmacological target for the design of novel pharmacological treatments in human UC.
Buanne
Pasquale
P
Department of Preclinical Pharmacology, Dompé pha r ma s p a, Via Campo di Pile, 67100, L'Aquila, Italy.
Di Carlo
Emma
E
Caputi
Lorenzo
L
Brandolini
Laura
L
Mosca
Marco
M
Cattani
Franca
F
Pellegrini
Luigi
L
Biordi
Leda
L
Coletti
Gino
G
Sorrentino
Carlo
C
Fedele
Guido
G
Colotta
Francesco
F
Melillo
Gabriella
G
Bertini
Riccardo
R
D000818:Animals; D054360:Chemokine CXCL1 / Q000378:metabolism; D054426:Chemokine CXCL2 / Q000378:metabolism; D002908:Chronic Disease; D003093:Colitis, Ulcerative / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D015994:Incidence; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009504:Neutrophils / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D023063:Receptors, Interleukin-8B / Q000235:genetics / Q000502:physiology*
D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; C475895:Cxcl1 protein, mouse; C404915:Cxcl2 protein, mouse; D023063:Receptors, Interleukin-8B; D016264:Dextran Sulfate; D009195:Peroxidase