AMD3100, a CxCR4 Antagonist, Attenuates Allergic Lung Inflammation and Airway Hyperreactivity

Abstract

The role of specific chemokine receptors during allergic asthmatic responses has been relatively undefined. A number of receptors are preferentially expressed on Th2 cells, including CCR4, CCR8, and CxCR4. In the present study, we have examined the role of CxCR4 in the development of cockroach allergen-induced inflammation and airway hyperreactivity in a mouse model of asthma. Using a specific inhibitor of CxCR4, AMD3100, our results indicate that blocking this receptor has a significant effect in down-regulating the inflammation and pathophysiology of the allergen-induced response. Treatment of allergic mice with AMD3100 significantly reduced airway hyperreactivity, peribronchial eosinophilia, and the overall inflammatory responses. In addition, there was a shift in the cytokine profile that was observed in the AMD3100-treated animals. Specifically, there was a significant reduction in interleukin-4 and interleukin-5 levels and a significant increase in interleukin-12 and interferon-␥ levels within the lungs of treated allergic mice. Furthermore, there was a significant alteration in the local chemokine production of CCL22 (MDC) and CCL17 (TARC), two chemokines previously shown to be important in Th2-type allergen responses. Overall, specifically blocking CxCR4 using AMD3100 reduced a number of pathological parameters related to asthmatic-type inflammation.

CXCL12-CXCR4 Promotes Proliferation and Invasion of Pancreatic Cancer Cells

“…Interestingly, the CXCR4 receptor can be blocked by the specific inhibitor AMD3100. Through its blockade on CXCR4, AMD3100 can inhibit invasion and metastasis of malignant cells (Blanco et al, 2000) and has fewer side effects in clinical application (Lukacs et al, 2002).…”

Thioredoxin suppresses airway inflammation independently of systemic Th1/Th2 immune modulation

“…Furthermore, recent studies demonstrate that MIF can act as a noncognate ligand for CXCR4 [44,45]. Eosinophils express CXCR4 and migrate toward CXCR4 ligand SDF-1 to a similar extent as eotaxin [46] and CXCR4 blockade suppresses eosinophil migration into the asthmatic lung [47]. Although further studies are needed to differentiate between MIF and SDF-1 in the eosinophil migration into the lung, MIF can act as a chemoattractant for eosinophils [48], suggesting a direct role for MIF in eosinophil migration into inflamed lung tissue.…”

Pathogen induction of CXCR4/TLR2 cross-talk impairs host defense function

“…Because the killing of P. gingivalis by mouse phagocytes is mediated by NO (18), we first determined whether CXCR4 inhibits induction of NO (measured as NO 2 Ϫ , its stable metabolite) by P. gingivalis in mouse macrophages. Indeed, CXCR4 blockade with AMD3100 [highly specific antagonist of both human and mouse CXCR4 (19,20)] or anti-CXCR4 mAb resulted in significantly enhanced levels of NO 2 Ϫ (Fig. 6A), the production of which depended heavily on TLR2 (Fig.…”