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.
Department of Preclinical Pharmacology, Dompé pha r ma s p a, Via Campo di Pile, 67100, L'Aquila, Italy.
Pasquale
P
Buanne
Emma
E
Di Carlo
Lorenzo
L
Caputi
Laura
L
Brandolini
Marco
M
Mosca
Franca
F
Cattani
Luigi
L
Pellegrini
Leda
L
Biordi
Gino
G
Coletti
Carlo
C
Sorrentino
Guido
G
Fedele
Francesco
F
Colotta
Gabriella
G
Melillo
Riccardo
R
Bertini
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