Impaired neutrophil migration underpins host susceptibility to infectious colitis

Abstract

Citrobacter rodentium models infection with enteropathogenic Escherichia coli and ulcerative colitis (UC). While C57BL/6 (C57) mice recover, C3H/HeN (C3H) mice succumb to infection, partially due to increased colonic neutrophil elastase activity, also seen in UC patients; however, the underlying cause was unknown. Here, we found that bone marrow, blood, and colonic C57 neutrophils expressed (CD)11b^Hi and reached the infected colonic lumen, where they underwent productive NETosis. In contrast, while the number of C3H neutrophils increased in the bone marrow, blood, and colon, they remained CD11b^Lo and got trapped in the submucosa, away from C. rodentium, where they underwent harmful NETosis. CD11b^Lo neutrophils in C3H mice infected with CR_i9, which triggers expression of neutrophil chemoattractants, reached the colonization site, resulting in host survival. UC patient neutrophils also displayed decreased levels of the activation/differentiation markers CD16/CXCR4. These results, suggesting that neutrophil malfunction contributes to exacerbated colitis, provide insight for future therapeutic prospects.