Carbon Monoxide Impairs CD11b+Ly-6Chi Monocyte Migration from the Blood to Inflamed Pancreas via Inhibition of the CCL2/CCR2 Axis.

Acute pancreatitis (AP) is a sterile inflammation, in which inflammatory monocytes (CD11b+Ly-6Chi) are recruited into the inflamed tissue at the onset of disease. Monocyte infiltration and activation at the site of inflammation are critical to the pathogenesis of AP. Our previous studies have shown a protective role for CO in AP, which is partially mediated by inhibition of macrophage activation via TLR4 signaling. In the current study, to gain a better understanding of CO's therapeutic effect, we further investigated whether CO could affect inflammatory monocyte trafficking during AP. In a mouse model of AP, we found that treatment with CO-releasing molecule-2 (CORM-2) impaired recruitment of inflammatory monocytes, but not that of neutrophils, from peripheral blood to inflamed pancreas. During the early stage of AP, a single dose of CORM-2 decreased pancreatic CCL2 and soluble ICAM-1 expression. In addition, using in vivo and in vitro experiments, we found that CORM-2 had the ability to inhibit CD11b+Ly-6Chi monocyte migration via blockade of CCR2 endocytosis. Notably, we showed that CORM-2 inhibited CCR2 endocytosis of inflammatory monocytes (CD14hiCD16-) from AP patients. Taken together, our results highlighted CO's effect on inflammatory monocyte trafficking, shedding additional light on its therapeutic potential in AP.