CXCR1 and CXCR2 are two chemokine receptors in Neutrophils. They play an important role in the pathogenesis of inflammatory responses. Specially, IL-8/CXCL8 and GCP-2/CXCL6 bind and activate CXCR1 and CXCR2, promoting neutrophil migration. In addition, CXCL1, -2, -3, -5, and -7 are potent agonists only for CXCR2. Besides, it has been well characterized that activation of CXCR1 and CXCR2 is able to promote neutrophil degranulation and chemotaxis at sites of inflammation. However, during the process, CXCR1 functions in superoxide production, and CXCR2 seems to be involved in the initiation of this cell migration.
Researchers reported that selective and competitive CXCR2 antagonist SB225002 could reduce neutrophil recruitment in many pathophysiological states. Likewise, CXCR2-knockout mice have shown limited mucosal damage and reduced inflammatory signs following dextran sulfate sodium-induced colitis.
In the study, the authors aimed to investigate the potential beneficial effects of SB225002 in TNBS-induced colitis in mice.
As a result, after colitis establishment, SB225002 administration significantly reduced colon edema, attenuated macroscopic and histological damage. It also restored colon length, and recovered mouse body weight, greatly reducing mortality. In addition, mice treated with dexamethasone did not recover body weight, unlike SB225002 treated groups, suggesting that the CXCR2 antagonist produces less intense side-effects. However, SB225002 treatment highly decreased mucosal injury, without interfering in EPO activity.
Moreover, SB225002 significantly increased the level of IL-4 and IL-10 in colons from mice. Of high interest, SB225002 was able to attenuate TNBS-induced colitis after the establishment of inflammation. The selective nonpeptide CXCR2 antagonist SB225002 is a potential candidate for the treatment of IBD.