Chemokine Ligand-3 (CCL3) as a Novel Mediator of Inflammatory Bowel Disease Activity

Abstract

Background and Aims

Inflammatory bowel disease (IBD) is characterized by dysregulation of the immune system, driven in part by pro-inflammatory macrophage polarization. Chemokine ligand-3 (CCL3) is a chemokine known to mediate inflammation and act to polarize M1 macrophages at the site of inflammation. CCL3 is upregulated in patients with IBD, but its contribution to disease pathophysiology beyond that is unknown. Our hypothesis was that CCL3 expression increases at sites of more intense inflammation in biopsies from patients with IBD and it mediates inflammation through neutrophils and M1 macrophages.

Methods

Gastrointestinal mucosal biopsies from patients with IBD in varying states of inflammation were immunostained for CCL3 and co-immunostained for C-C motif chemokine receptor 1 (CCR1) and C-C motif chemokine receptor 5 (CCR5). Imaging mass cytometry was performed to identify CCL3-expressing cell spatial relationships.

Results

Immunohistochemistry found that CCL3 was expressed in a variety of cell types in patients with both ulcerative colitis and Crohn’s disease. CCL3 receptors, CCR1 and CCR5, were widely expressed as well, with co-expression of CCL3 occurring in a subset of these cells that was higher than that of CCL3/CCR5. Imaging mass cytometry highlighted a positive correlation between CCL3 and the severity of inflammation of IBD patient biopsies. The majority of CCL3-positive cells were neutrophils and macrophages (in particular, proinflammatory M1 macrophages), but there was also expression on eosinophils and epithelial cells.

Conclusion

CCL3 is expressed in many cell types in the gut mucosa in patients with IBD and is positively associated with the severity of local inflammation. CCL3-mediated effects in IBD may occur primarily through the CCR1 signaling pathway, leading to attraction and polarization of macrophages and neutrophils.